Diaryl ureas for treating virus infections

ABSTRACT

The present invention relates to pharmaceutical compositions for treating virus infections and/or diseases caused by virus infections comprising at least a diaryl urea compound optionally combined with at least one additional therapeutic agent. Useful combinations include e.g. BAY 43-9006 as a diaryl urea compound.

The present invention relates to pharmaceutical compositions fortreating virus infections and/or diseases caused thereby comprising atleast a diaryl urea compound optionally combined with at least oneadditional therapeutic agent. Useful combinations include e.g. BAY43-9006 as a diaryl urea compound.

BAY 43-9006 refers to4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide and is species of diaryl urea compounds which arepotent anti-cancer and anti-angiogenic agents that possess variousactivities, including inhibitory activity on the VEGFR, PDGFR, rat p38,and/or fit-3 kinase signaling molecules. See, e.g., WO 2004/113274 andWO 2005/000284.

SARS (severe acute respiratory syndrome) is a disease caused by aninfection with SARS coronavirus (SARS-CoV) which gets public importancein the last years. For infected patients the therapeutic standard oftoday is, however, low.

A typical coronavirus is represented by e.g. the mouse hepatitis virus(MHV) which induces the p38 kinase which is part of the MAPK pathway ininfected cells (S. Banerjee et al. J. Viral. 2002, 76, 5937-5948).Furthermore recent results show that also SARS-CoV induces the signalpathway of p38 MAPK in permissive cells (Mizutani et al. Biochem.Biophys. Res. Commun. 2004, 319, 1228-1234).

A known standard therapy of HIV (human immunodeficiency virus)infections is HAART (highly active antiretroviral therapy) wherein acombination of several antiretroviral drugs (protease inhibitors andantiretroviral drugs) are administered to infected patients (e.g. acombination of indinavir, zidovudine and lamivudin). The drugs inhibitthe ability of the virus to multiply in the body and slow thedevelopment of AIDS (acquired immunodeficiency syndrome).

Furthermore it is known that the p38 kinase inhibitor RWJ 67657suppresses the replication of HIV and the cellular pathogenesis of theinfection (K. Muthumani et al. AIDS, 2004, 18, 739-748).

Hepatitis viruses such as HBV and HCV modulate the MAPK signal pathwayin infected cells (M. Panteva et al. Virus Research 2003, 92, 131). Apermanent activation of the RAF/MEK/ERK signal pathway is detected incells expressing HCV Core Protein (S. Giambartolomei et al., Oncogene,2001, 20, 2607) and an increased level of N-Ras is important for themaintenance of the replication of HCV (P. Mannova, L. Beretta, J. Virol.2005, 79 (14), 8742) wherein Ras is affected by Raf. It is also knownthat the integrity of the RAF/MEK signal cascade is a precondition forthe replication of HBV (L. Stockl, Oncogene, 2003, 22 (17), 260).Influenza viruses such as type A, B or C belong to group ofOrthomyxoviruses and cause every year flu epidemics effecting up to10,000 cases of death per year in Germany. Relevant cellular targets fora therapy are known (S. Ludwig et al., Trends Mol. Med., 2003, 46). Thep38 MAPK signal pathway is induced in mouse cells infected withinfluenza A virus (I. Mori et al., J. Gen. Virol. 2003, 84, 2401).Furthermore inhibition of MEK inhibit the proliferation of influenza Vvirus in cell cultures (S. Ludwig et al. FEBS Letters, 2004, 561, 37).

The viruses of the Herpesviridae family comprise viruses of thesub-families Alphaherpesviridae (e.g. simplcxviruses such as humanherpes simplex viruses and varicelloviruses such as human varizellazoster virus), Betaherpesviridae (e.g. cytomegalovirus and roseolovirus)and Gamma-herpesviridae (e.g. Epstein-Barr virus). Such virus infectionscan cause e.g. infections of the lymphatic system of the outergenitalia, the lips, the briars (herpesencephalitis) or the peripheralnerves.

A number of herpeviruses use the cellular signal pathways of MAPK/ERKand p38 MAPK, e.g. infection with herpes simplex virus induce theactivation of the p38 MAPK and SAPK/JNK signal pathway (G. Zachos etal., J. Biol. Chem. 1999, 274, 5097). Inhibitors of the MAPK/ERK or thep38 MAPK pathway inhibit the activation of early promoters of the humancytomegalovirus (J. Chen et al. J. Virol., 2002, 76 (10), 4873).

The viruses of the Papovaviridae family comprise the genuspapillomaviruses and include a “high risk” group of viruses (e.g.species HPV 16, 18) and a “low risk” group (e.g. HPV 6, 11). Humanpapillomaviruses induce neoplasm of the dermis and can cause theformation of papillomas. Virus infections of the “low risk” group,however, are associated with malignant tumour diseases (e.g. zervixcancer). Types of the “low risk” group cause e.g. anogenital warts. Anactivation of the MAPK signal pathway is detected in human papillomasinfected with papillomaviruses (D. Johnston et al., Cancer Res., 1999,59 (4), 968).

Pox were one of the most dreaded diseases in history and deemed to beexterminated in 1977 after introduction of immunisation. Todaypoxviruses such as the molluscum contagiosum virus and poxvirusespathogenic for animals play a role. The viruses of the Poxyiridae familyinclude the sub-family Chordopoxyiridae and comprise avipoxvirus,capripoxvirus, lepripoxvirus, suipoxvirus, parapoxvirus,molluscipoxvirus and orthopoxvirus. Such virus infections can cause e.g.smallpox. Cellular targets are known for the therapy of poxvirusinfections (H. Yang et al., J. Clin. Invest, 2005, 115 (2), 379).

The genus flavivirus and pestivirus especially the yellow fever virus,denguevirus 1 to 4, west nile fever virus, spring-summer encephalitisvirus, Omsk-hemorrhagic fever virus, bovine virus-diarrhea-virus andswine fever virus, belong to the Flaviviridae family. Such virusinfections can cause e.g. encephalitis and encephalomyelitis.

Activation of the p38 MAPK signal pathway plays an important role forthe interaction of Flaviviridae viruses and the host cells (C. Chen etal., J. Gen. Viral. 2002, 83, 1897).

The genus enterovirus, cardiovirus, rhinovirus, aphtovirus andhepatovirus especially the polio-viruses, coxsackieviruses,coxsackieviruses, human echoviruses, human enteroviruses, humanrhinoviruses and hanks viruses, belong to the Picornaviridae family.Such virus infections can cause e.g. in humans aseptic meningitis,poliomyelitis, herpangina, pleurodynia (Bornholm disease), myositis,rhabdomyolysis, diabetes type I, summer fever and myocarditis.Furthermore in animals rhinoviruses, and the foot and mouth diseaseviruses can be caused by such infections.

It is shown that inhibition of p38 MAPK can inhibit the replication ofPicornaviridae viruses (K. Hirasawa et al., J. Virol. 2003, 77 (10),5649-5656).

The present invention provides pharmaceutical compositions for treatingvirus infections and/or diseases caused thereby comprising at least onecompound of formula I and optionally at least one further therapeuticagent.

The present invention provides a therapeutic method which treat virusinfections according to the present invention and/or diseases caused bysuch infections of infected patients more effectively compared tocurrent therapies and therefore is superior to current therapies. Thepresent invention can be used e.g. by administering a diaryl ureacompound of formula I and optionally a further therapeutic agent,pharmaceutically-acceptable salts thereof, and derivatives thereof, etc.

The present invention provides pharmaceutical compositions for treatingSARS-CoV infections and/or SARS itself comprising at least one compoundof formula I and optionally at least one further therapeutic agent.

The present invention provides a therapeutic method which treat SARS-CoVinfections and/or SARS itself of infected patients more effectivelycompared to current therapies and therefore is superior to currenttherapies. The present invention can be used e.g. by administering adiaryl urea compound of formula I and optionally a further therapeuticagent, pharmaceutically-acceptable salts thereof, and derivativesthereof, etc.

The present invention provides pharmaceutical compositions for treatingHIV infections and/or diseases caused by HIV infections comprising atleast one compound of formula I and optionally at least one furthertherapeutic agent.

The present invention provides a therapeutic method which treat HIVinfections and/or diseases caused by HIV infections of infected patientsmore effectively compared to current therapies and therefore is superiorto current therapies. The present invention can be used e.g. byadministering a diaryl urea compound of formula I and optionally afurther therapeutic agent, pharmaceutically-acceptable salts thereof,and derivatives thereof, etc.

The present invention provides pharmaceutical compositions for treatinghepatitis virus infections and/or diseases caused by hepatitis virusinfections comprising at least one compound of formula I and optionallyat least one further therapeutic agent.

The present invention provides a therapeutic method which treathepatitis virus infections and/or diseases caused by hepatitis virusinfections of infected patients more effectively compared to currenttherapies and therefore is superior to current therapies. The presentinvention can be used e.g. by administering a diaryl urea compound offormula 1 and optionally a further therapeutic agent,pharmaceutically-acceptable salts thereof, and derivatives thereof, etc.

The present invention provides pharmaceutical compositions for treatinginfluenza virus infections and/or diseases caused by influenza virusinfections comprising at least one compound of formula I and optionallyat least one further therapeutic agent.

The present invention provides a therapeutic method which treatinfluenza virus infections and/or diseases caused by influenza virusinfections of infected patients more effectively compared to currenttherapies and therefore is superior to current therapies. The presentinvention can be used e.g. by administering a diaryl urea compound offormula I and optionally a further therapeutic agent,pharmaceutically-acceptable salts thereof, and derivatives thereof, etc.

The present invention provides pharmaceutical compositions for treatinginfections by viruses of the Herpesviridae family (Herpesviridae virusesinfections) and/or diseases caused by such infections comprising atleast one compound of formula I and optionally at least one furthertherapeutic agent.

The present invention provides a therapeutic method which treatElerpesviridae viruses infections and/or diseases caused by suchinfections of infected patients more effectively compared to currenttherapies and therefore is superior to current therapies. The presentinvention can be used e.g. by administering a diaryl urea compound offormula I and optionally a further therapeutic agent,pharmaceutically-acceptable salts thereof, and derivatives thereof, etc.

The present invention provides pharmaceutical compositions for treatinginfections by viruses of the Papovaviridae family (Papovaviridae virusesinfections) and/or diseases caused by such infections comprising atleast one compound of formula I and optionally at least one furthertherapeutic agent.

The present invention provides a therapeutic method which treatPapovaviridae viruses infections and/or diseases caused by suchinfections of infected patients more effectively compared to currenttherapies and therefore is superior to current therapies. The presentinvention can be used e.g. by administering a diaryl urea compound offormula I and optionally a further therapeutic agent,pharmaceutically-acceptable salts thereof, and derivatives thereof, etc.

The present invention provides pharmaceutical compositions for treatinginfections by viruses of families selected from the group consisting ofReoviridae, Astroviridae, Bunyaviridae, Filoviridae, Arenaviridae,Rhabdoviridae, Togaviridae, Paramyxoviridae and unclassified prionsand/or diseases caused by such infections comprising at least onecompound of formula I and optionally at least one further therapeuticagent.

The present invention provides pharmaceutical compositions for treatinginfections by viruses of the Poxyiridae family (Poxyiridae virusesinfections) and/or diseases caused by such infections comprising atleast one compound of formula I and optionally at least one furthertherapeutic agent.

The present invention provides a therapeutic method which treatPoxyiridae viruses infections and/or diseases caused by such infectionsof infected patients more effectively compared to current therapies andtherefore is superior to current therapies. The present invention can beused e.g. by administering a diaryl urea compound of formula I andoptionally a further therapeutic agent, pharmaceutically-acceptablesalts thereof, and derivatives thereof, etc.

The present invention provides pharmaceutical compositions for treatinginfections by viruses of the Flaviviridae family (Flaviviridae virusesinfections) and/or diseases caused by such infections comprising atleast one compound of formula I and optionally at least one furthertherapeutic agent.

The present invention provides a therapeutic method which treatFlaviviridae viruses infections and/or diseases caused by suchinfections of infected patients more effectively compared to currenttherapies and therefore is superior to current therapies. The presentinvention can be used e.g. by administering a diaryl urea compound offormula I and optionally a further therapeutic agent,pharmaceutically-acceptable salts thereof, and derivatives thereof, etc.

The present invention provides pharmaceutical compositions for treatinginfections by viruses of the Picornaviridae family (Picornaviridaeviruses infections) and/or diseases caused by such infections comprisingat least one compound of formula I and optionally at least one furthertherapeutic agent.

The present invention provides a therapeutic method which treatPicornaviridae viruses infections and/or diseases caused by suchinfections of infected patients more effectively compared to currenttherapies and therefore is superior to current therapies. The presentinvention can be used e.g. by administering a diaryl urea compound offormula I and optionally a further therapeutic agent,pharmaceutically-acceptable salts thereof, and derivatives thereof, etc.

The compounds with the structure of formula (I), pharmaceuticallyacceptable salts, polymorphs, solvates, hydrates metabolites andprodrugs thereof, including diastereoisomeric forms (both isolatedstereoisomers and mixtures of stereoisomers) are collectively referredto herein as the “compounds of formula I”.

Formula (I) is as follows:

-   wherein-   Q is —C(O)R.-   R_(x) is hydroxy, C₁₋₄ alkyl, C₁₋₄alkoxy or NR_(a)R_(b),-   R_(a) and R_(b) are independently:    -   a) hydrogen;    -   b) C₁₋₄ alkyl, optionally substituted by -hydroxy, —C₁₋₄ alkoxy,        -   a heteroaryl group selected from pyrrole, furan, thiophene,            imidazole, pyrazole, thiazole, oxazole, isoxazole,            isothiazole, triazole, tetrazole, thiadiazole, oxadiazole,            pyridine, pyrimidine, pyridazine, pyrazine, triazine,            benzoxazole, isoquioline, quinolines and imidazopyrimidine        -   a heterocyclic group selected from tetrahydropyran,            tetrahydrofuran, 1,3-dioxolane, 1,4-dioxane, morpholine,            thiomorpholine, piperazine, piperidine, piperidinone,            tetrahydropyrimidone, pentamethylene sulfide, tetramethylene            sulfide, dihydropyrane, dihydrofuran, and dihydrothiophene,        -   amino, —NH₂, optionally substituted by one or two C₁₋₄ alkyl            groups, or -phenyl,    -   c) phenyl optionally substituted with -halogen, or        -   amino, —NH₂, optionally substituted by one or two C₁₋₄            alkyl, or    -   d) a heteroaryl group selected from pyrrole, furan, thiophene,        imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole,        triazole, tetrazole, thiadiazole, oxadiazole, pyridine,        pyrimidine, pyridazine, pyrazine, triazine, benzoxazole,        isoquioline, quinoline and imidazopyrimidine;-   A is optionally substituted phenyl, pyridinyl, naphthyl,    benzoxazole, isoquioline, quinoline or imidazopyrimidine;-   B is optionally substituted phenyl or naphthyl:-   L is a bridging group which is —S— or —O—;-   m is 0, 1, 2 or 3, and    -   each R² is independently C₁₋₅ alkyl, C₁₋₅ haloalkyl, C₁₋₃        alkoxy, N-oxo or N-hydroxy.

Structures of optionally substituted phenyl moieties for A of formula(I) which are of particular interest include structures of formula 1xx:

Structures of optionally substituted pyridinyl moieties for A of formula(I) which are of particular interest include structures of formula 1x:

Structures of optionally substituted naphthyl moieties for A of formula(I) which are of particular interest include structures of formula 1y:

The structure 1y represents that the substituents R³ can appear on anycarbon atom in either ring which has a valence that is otherwisecomplete with a hydrogen atom as a substituent. The bond to the ureagroup can also be through any carbon atom on either ring which has avalence that is otherwise complete with a hydrogen atom as asubstituent.

B is optionally substituted phenyl or naphthyl. Structures of optionallysubstituted phenyl or naphthyl moieties for B of formula (I) which areof particular interest include structures 2a and 2b:

The structures 2a and 2b represent that the substituents R¹ can appearon any carbon atom in the structure which has a valence that isotherwise complete with a hydrogen atom as a substituent and the bond tothe urea group can be through any carbon atom in the structure which hasa valence that is otherwise complete with a hydrogen atom as asubstituent.

In a class of embodiments of this invention, B is substituted by atleast one halogen substituent. In another class of embodiments, R_(x) isNR_(a)R_(b), and R_(a) and R_(b) are independently hydrogen or C₁₋₄alkyl optionally substituted by hydroxy and L is a bridging group whichis —S— or —O—.

The variable p is 0, 1, 2, 3, or 4, typically 0 or 1. The variable n is0, 1, 2, 3, 4, 5 or 6, typically 0, 1, 2, 3 or 4. The variable m is 0,1, 2 or 3, typically 0.

Each R¹ is independently: halogen, C₁₋₅ haloalkyl, NO₂, C(O)NR⁴R⁵, C₁₋₆alkyl, C₁₋₆ dialkylamine, C₁₋₃ alkylamine, CN, amino, hydroxy or C₁₋₅alkoxy. Where present, R¹ is more commonly halogen and of the halogens,typically chlorine or fluorine, and more commonly fluorine.

Each R² is independently: C₁₋₅ alkyl, C₁₋₅ haloalkyl, C₁₋₃ alkoxy, N-oxoor N-hydroxy. Where present, R² is typically methyl or trifluoromethyl.

Each R³ is independently selected from halogen, R⁴, OR⁴, S(O)R⁴, C(O)R⁴,C(O)NR⁴R⁵, oxo, cyano or nitro (NO₂).

R⁴ and R⁵ are independently selected from hydrogen, C₁₋₄ alkyl, and upto per-halogenated C₁₋₆ alkyl.

Other examples of A include: 3-tert butyl phenyl, 5-tertbutyl-2-methoxyphenyl, 5-(trifluoromethyl)-2-phenyl,3-(trifluoromethyl)-4-chlorophenyl, 3-(trifluoromethyl)-4-bromo-phenyland 5-(trifluoromethyl)-4-chloro-2 methoxyphenyl.

Other examples of B include:

Preferably the urea group —NH—C(O)—NH— and the bridging group, L, arenot bound to contiguous ring carbons of B, but rather have 1 or 2 ringcarbons separating them.

Examples of R¹ groups include fluorine, chorine, bromine, methyl, NO₂,C(O)NH₂, methoxy, SCH₃, trifluoromethyl, and methanesulfonyl.

Examples of R² groups include methyl, ethyl, propyl, oxygen, and cyano.

Examples of R³ groups include trifluoromethyl, methyl, ethyl, propyl,butyl, isopropyl, tert-butyl, chlorine, fluorine, bromine, cyano,methoxy, acetyl, trifluoromethanesulfonyl, trifluoromethoxy, andtrifluoromethylthio.

A class of compounds of interest are of formula II below

wherein Ra and Rb are independently hydrogen and C₁-C₄ alkyl,

B of formula II is

wherein the urea group, —NH—C(O)—NH—, and the oxygen bridging group arenot bound to contiguous ring carbons of B, but rather have 1 or 2 ringcarbons separating them,and A of formula (II) is

wherein the variable n is 0, 1, 2, 3 or 4.

R³ is trifluoromethyl, methyl, ethyl, propyl, butyl, isopropyl,tert-butyl, chlorine, fluorine, bromine, cyano, methoxy, acetyl,trifluoromethanesulfonyl, trifluoromethoxy, or trifluoromethylthio.

In a subclass of such compounds, each R³ substituent on A of formula IIis selected from chlorine, trifluoromethyl, tert-butyl or methoxy.

In another subclass of such compounds, A of formula II is

and B of formula II is phenylene, fluoro substituted phenylene ordifluoro substituted phenylene.

Another class of compounds of interest includes compounds having thestructure of formulae X below wherein phenyl ring “B” optionally has onehalogen substituent.

For the compounds of formula X, R², in and A are as defined above forformula I. The variable “In” is preferably zero, leaving C(O)NHCH₃ asthe only substituent on the pyridinyl moiety. Preferred values for A aresubstituted phenyl which have at least one substituent, R³. R³ ispreferably halogen, preferably Cl or F, trifluoromethyl and/or methoxy.

A subclass of compounds of interest includes compounds having thestructure of formulas Z1 and Z2 below:

Preferably used as compound of formula I according to the invention is4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide (BAY 43-9006) or the p-toluenesulfonic acid salt of4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide (tosylate salt of compound (I)). More preferably thep-toluenesulfonic acid salt of4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide exists for at least 80% in the stable polymorph I.Most preferably the p-toluenesulfonic acid salt of4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide exists for at least 80% in the stable polymorph I andin a micronized form.

Micronization can be achieved by standard milling methods, preferably byair chat milling, known to a skilled person. The micronized form canhave a mean particle size of from 0.5 to 10 μm, preferably from 1 to 6μm, more preferably from 1 to 3 μm. The indicated particle size is themean of the particle size distribution measured by laser diffractionknown to a skilled person (measuring device: HELOS, Sympatec).

The process for preparing the p-toluenesulfonic acid salt of4{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide and its stable polymorph I are described in the patentapplications EP 04023131.8 and EP 04023130.0.

When any moiety is “substituted”, it can have up to the highest numberof indicated substituents and each substituent can be located at anyavailable position on the moiety and can be attached through anyavailable atom on the substituent. “Any available position” means anyposition on the moiety that is chemically accessible through means knownin the art or taught herein and that does not create an unstablemolecule, e.g., incapable of administration to a human. When there aretwo or more substituents on any moiety, each substituent is definedindependently of any other substituent and can, accordingly, be the sameor different.

The term “optionally substituted” means that the moiety so modified maybe either unsubstituted, or substituted with the identifiedsubstituent(s).

It is understood that the term “hydroxy” as a pyridine substituentincludes 2-, 3-, and 4-hydroxypyridine, and also includes thosestructures referred to in the art as 1-oxo-pyridine, 1-hydroxy-pyridineor pyridine N-oxide.

Where the plural form of the word compounds, salts, and the like, isused herein, this is taken to mean also a single compound, salt, or thelike.

The term C₁₋₆ alkyl, unless indicated otherwise, means straight,branched chain or cyclic alkyl groups having from one to six carbonatoms, which may be cyclic, linear or branched with single or multiplebranching. Such groups include for example methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl,cyclobutyl and the like.

The term C₁₋₆ haloalkyl, unless indicated otherwise, means a saturatedhydrocarbon radical having up to six carbon atoms, which is substitutedwith a least one halogen atom, up to perhalo. The radical may be cyclic,linear or branched with single or multiple branching. The halosubstituent(s) include fluoro, chloro, bromo, or iodo. Fluoro, chloroand bromo are preferred, and fluoro and chloro are more preferred. Thehalogen substituent(s) can be located on any available carbon. When morethan one halogen substituent is present on this moiety, they may be thesame or different. Examples of such halogenated alkyl substituentsinclude but are not limited to chloromethyl, dichloromethyl,trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl, and 1,1,2,2-tetrafluoroethyl, and the like.

The term C₁₋₆ alkoxy, unless indicated otherwise, means a cyclic,straight or branched chain alkoxy group having from one to six saturatedcarbon atoms which may be cyclic, linear or branched with single ormultiple branching, and includes such groups as methoxy, ethoxy,n-propoxy, isopropoxy, butoxy, pentoxy and the like. It also includeshalogenated groups such as 2,2-dichloroethoxy, trifluoromethoxy, and thelike.

Halo or halogen means fluoro, chloro, bromo, or iodo. Fluoro, chloro andbromo are preferred, and fluoro and chloro are more preferred.

C₁₋₃alkylamine, unless indicated otherwise, means methylamino,ethylamino, propylamino or isopropylamino.

Examples of C₁₋₆ dialkylamine include but are not limited todiethylamino, ethyl-isopropylamino, methyl-isobutylamino anddihexylamino.

The term heteroaryl refers to both monocycle and bicycle heteroarylrings. Monocycle heteroaryl means an aromatic monocyclic ring having 5to 6 ring atoms and 1-4 hetero atoms selected from N, O and S, theremaining atoms being carbon. When more than one hetero atom is presentin the moiety, they are selected independently from the other(s) so thatthey may be the same or different. Monocycle heteroaryl rings include,but are not limited to pyrrole, furan, thiophene, imidazole, pyrazole,triazole, oxazole, isoxazole, isothiazole, triazole, tetrazole,thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, andtriazine.

Bicyclic heteroaryl means fused bicyclic moieties where one of the ringsis chosen from the monocyclic heteroaryl rings described above and thesecond ring is either benzene or another monocyclic heteroaryl ringdescribed above. When both rings in the bicyclic moiety are heteroarylrings, they may be the same or different, as long as they are chemicallyaccessible by means known in the art. Bicycle heteroaryl rings includesynthetically accessible 5-5, 5-6, or 6-6 fused bicyclic aromaticstructures including, for example but not by way of limitation,benzoxazole (fused phenyl and oxazole), quinoline (fused phenyl andpyridine), imidazopyrimidine (fused imidazole and pyrimidine), and thelike.

Where indicated, the bicycle heteroaryl moieties may be partiallysaturated. When partially saturated either the monocyclic heteroarylring as described above is fully or partially saturated, the second ringas described above is either fully or partially saturated or both ringsare partially saturated.

The term “heterocyclic group”, unless indicated otherwise, meansmonocyclic and bicyclic moieties containing at least one atom selectedfrom oxygen, nitrogen and sulfur, which is saturated or partiallysaturated, and includes, by no way of limitation, tetrahydropyran,tetrahydrofuran, dioxolane, 1,4-dioxane, morpholine, thiomorpholine,piperazine, piperidine, piperidinone, tetrahydropyrimidone,pentamethylene sulfide, tetramethylene sulfide, dihydropyrane,dihydro-furan, dihydrothiophene and the like.

The term “C₁₋₃ alkyl-phenyl” includes, for example, 2-methylphenyl,isopropylphenyl, 3-phenylpropyl, or 2-phenyl-1-methylethyl. Substitutedexamples include 2-[2-chlorophenyl]ethyl, 3,4-dimethylphenylmethyl, andthe like.

Unless otherwise stated or indicated, the term “aryl” includes 6-12membered mono or bicyclic aromatic hydrocarbon groups (e.g., phenyl,naphthalene, azulene, indene group) having 0, 1, 2, 3, 4, 5 or 6substituents.

The compounds of formula (I) may contain one or more asymmetric centers,depending upon the location and nature of the various substituentsdesired. Asymmetric carbon atoms may be present in the (R) or (S)configuration or (R,S) configuration. In certain instances, asymmetrymay also be present due to restricted rotation about a given bond, forexample, the central bond adjoining two substituted aromatic rings ofthe specified compounds. Substituents on a ring may also be present ineither cis or trans form. It is intended that all such configurations(including enantiomers and diastereomers), are included within the scopeof the present invention. Preferred compounds are those with theabsolute configuration of the compound of formula (I) which produces themore desirable biological activity. Separated, pure or partiallypurified isomers or racemic mixtures of the compounds of this inventionare also included within the scope of the present invention. Thepurification of said isomers and the separation of said isomericmixtures can be accomplished by standard techniques known in the art.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, ditoluoyltartaric andcamphorsulfonic acid. Mixtures of diastereoisomers can be separated intotheir individual diastereomers on the basis of their physical and/orchemical differences by methods known in the art, for example, bychromatography or fractional crystallization. The optically active basesor acids are then liberated from the separated diastereomeric salts. Adifferent process for separation of optical isomers involves the use ofchiral chromatography (e.g., chiral HPLC columns), with or withoutconventional derivation, optimally chosen to maximize the separation ofthe enantiomers. Suitable chiral HPLC columns are manufactured byDiacel, e.g., Chiracel OD and Chiracel OJ among many others, allroutinely selectable. Enzymatic separations, with or withoutderivitization, are also useful. The optically active compounds offormula I can likewise be obtained by chiral syntheses utilizingoptically active starting materials.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as pharmaceutically acceptable salts, metabolitesand prodrugs. The term “pharmaceutically acceptable salt” refers to arelatively non-toxic, inorganic or organic acid addition salt of aCompound of the present invention. For example, see S. M. Berge, et al.“Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19. Pharmaceuticallyacceptable salts include those obtained by reacting the main compound,functioning as a base, with an inorganic or organic acid to form a salt,for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid,methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid,succinic acid and citric acid. Pharmaceutically acceptable salts alsoinclude those in which the main compound functions as an acid and isreacted with an appropriate base to form, e.g., sodium, potassium,calcium, magnesium, ammonium, and choline salts. Those skilled in theart will further recognize that acid addition salts of the claimedcompounds may be prepared by reaction of the compounds with theappropriate inorganic or organic acid via any of a number of knownmethods. Alternatively, alkali and alkaline earth metal salts areprepared by reacting the compounds of the invention with the appropriatebase via a variety of known methods.

Representative salts of the compounds of this invention include theconventional non-toxic salts and the quaternary ammonium salts which areformed, for example, from inorganic or organic acids or bases by meanswell known in the art. For example, such acid addition salts includeacetate, adipate, alginate, ascorbate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate,maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate,nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate,tartrate, thiocyanate, tosylate, trifluoromethanesulfonate, andundecanoate.

Base salts include alkali metal salts such as potassium and sodiumsalts, alkaline earth metal salts such as calcium and magnesium salts,and ammonium salts with organic bases such as dicyclohexylamine andN-methyl-D-glucamine. Additionally, basic nitrogen containing groups maybe quaternized with such agents as lower alkyl halides such as methyl,ethyl, propyl, and butyl chlorides, bromides and iodides; dialkylsulfates like dimethyl, diethyl, and dibutyl sulfate; and diamylsulfates, long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides, aryl or aralkyl halides like benzyl andphenethyl bromides and others monosubstituted aralkyl halides orpolysubstituted aralkyl halides.

Solvates for the purposes of the invention are those forms of thecompounds where solvent molecules form a complex in the solid state andinclude, but are not limited to for example ethanol and methanol.Hydrates are a specific form of solvates, where the solvent molecule iswater.

Certain pharmacologically active agents can be further modified withlabile functional groups that are cleaved after in vivo administrationto furnish the parent active agent and the pharmacologically inactivederivatizing group. These derivatives, commonly referred to as prodrugs,can be used, for example, to alter the physicochemical properties of theactive agent, to target the active agent to a specific tissue, to alterthe pharmacokinetic and pharmacodynamic properties of the active agent,and to reduce undesirable side effects. Prodrugs of the inventioninclude, e.g., the esters of appropriate compounds of this inventionthat are well-tolerated, pharmaceutically acceptable esters such asalkyl esters including methyl, ethyl, propyl, isopropyl, butyl, isobutylor pentyl esters. Additional esters such as phenyl-C₁-C₅ alkyl may beused, although methyl ester is preferred.

Methods which can be used to synthesize other prodrugs are described inthe following reviews on the subject, which are incorporated herein byreference for their description of these synthesis methods:

-   Higuchi, T.; Stella, V. eds. Prodrugs As Novel Drug Delivery    Systems. ACS Symposium Series. American Chemical Society:    Washington, D.C. (1975).-   Roche, E. B. Design of Biopharmaceutical Properties through Prodrugs    and Analogs. American Pharmaceutical Association: Washington, D.C.    (1977).-   Sinkula, A. A.; Yalkowsky, S. H. J Pharm Sci. 1975, 64, 181-210.-   Stella, V. J.; Charman, W. N. Naringrekar, V. H. Drugs 1985, 29,    455-473.-   Bundgaard, H., ed. Design of Prodrugs. Elsevier: New York (1985).-   Stella, V. J.; Himmelstein, K. J. J. Med. Chem. 1980, 23, 1275-1282.-   Han, H-K; Amidon, G. L. AAPS Pharmsci 2000, 2, 1-11.-   Denny, W. A. Eur. J. Med. Chem. 2001, 36, 577-595.-   Wermuth, C. G. in Wermuth, C. G. ed. The Practice of Medicinal    Chemistry Academic Press: San Diego (1996), 697-715.-   Balant, L. P.; Doelker, E. in Wolff; M. E. ed. Burgers Medicinal    Chemistry And Drug Discovery John Wiley & Sons: New York (1997),    949-982.

The metabolites of the compounds of this invention include oxidizedderivatives of the compounds of formula I, II, X, Z1 and Z2, wherein oneor more of the nitrogens are substituted with a hydroxy group; whichincludes derivatives where the nitrogen atom of the pyridine group is inthe oxide form, referred to in the art as 1-oxo-pyridine or has ahydroxy substituent, referred to in the art as 1-hydroxy-pyridine.

General Preparative Methods

The particular process to be utilized in the preparation of thecompounds used in this embodiment of the invention depends upon thespecific compound desired. Such factors as the selection of the specificsubstituents play a role in the path to be followed in the preparationof the specific compounds of this invention. Those factors are readilyrecognized by one of ordinary skill in the art.

The compounds of the invention may be prepared by use of known chemicalreactions and procedures as described in the following publishedinternational applications WO 00/42012, WO03/047579, WO 2005/009961, WO2004/078747 and WO05/000284 and European patent applications EP04023131.8 and EP 04023130.0.

The compounds of the invention can be made according to conventionalchemical methods, and/or as disclosed below, from starting materialswhich are either commercially available or producible according toroutine, conventional chemical methods. General methods for thepreparation of the compounds are given below.

The preparation of ureas of formula (I) can be prepared from thecondensation of the two arylamine fragments and in the presence ofphosgene, di-phosgene, tri-phosgene, carbonyl-diimidazole, orequivalents in a solvent that does not react with any of the startingmaterials, as described in one or more of these published.Alternatively, compounds of formula (I) can be synthesized by reactingamino compounds) with isocyanate compounds as described in one or moreof published international applications described above.

The isocyanates are commercially available or can be synthesized fromheterocyclic amines according to methods commonly known to those skilledin the art [e.g. from treatment of an amine with phosgene or a phosgeneequivalent such as trichloromethyl chloroformate (diphosgene),bis(trichloromethyl)carbonate (triphosgene), or N,N′-carbonyldiimidazole(CDI); or, alternatively by a Curtius-type rearrangement of an amide, ora carboxylic acid derivative, such as an ester, an acid halide or ananhydride].

Aryl amines of formulas are commercially available, or can besynthesized according to methods commonly known to those skilled in theart. Aryl amines are commonly synthesized by reduction of nitroarylsusing a metal catalyst, such as Ni, Pd, or Pt, and H₂ or a hydridetransfer agent, such as formate, cyclohexadiene, or a borohydride(Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)).Nitroaryls may also be directly reduced using a strong hydride source,such as LiAlH₄ (Seyden-Penne. Reductions by the Alumina- andborohydrides in Organic Synthesis; VCH Publishers: New York (1991)), orusing a zero valent metal, such as Fe, Sn or Ca, often in acidic media.Many methods exist for the synthesis of nitroaryls (March. AdvancedOrganic Chemistry, 3^(rd) Ed.; John Wiley: New York (1985). Larock.Comprehensive Organic Transformations; VCH Publishers: New York (1989)).Nitro aryls are commonly formed by electrophilic aromatic nitrationusing HNO₃: or an alternative NO₂ ⁺ source.

Pyridine-1-oxides of formula (I) where the pyridine ring carries ahydroxy substituent on its nitrogen atom, and A, B, L are broadlydefined as above can be prepared from the corresponding pyridines usingoxidation conditions know in the art. Some examples are as follows:

-   peracids such as meta chloroperbenzoic acids in chlorinated solvents    such as dichloromethane, dichloroethane, or chloroform (Markgraf et    al., Tetrahedron 1991, 47, 183);-   (Me₃SiO)₂ in the presence of a catalytic amount of perrhenic acid in    chlorinated solvents such as dichloromethane (Coperet at al.,    Terahedron Lett. 1998, 39, 761);-   Perfluoro-cis-2-butyl-3-propyloxaziridine in several combinations of    halogenated solvents (Amone at al., Tetrahedron 1998, 54, 7831);-   Hypofluoric acid-acetonitrile complex in chloroform (Dayan et al.,    Synthesis 1999, 1427);-   Oxone, in the presence of a base such as KOH, in water (Robker et    al., J. Chem. Res., Synop. 1993, 10, 412);-   Magnesium monoperoxyphthalate, in the presence of glacial acetic    acid (Klemm at al., J. Heterocylic Chem. 1990, 6, 1537);-   Hydrogen peroxide, in the presence of water and acetic acid (Lin A.    J., Org. Prep. Proced. Int. 1991, 23(1), 114);-   Dimethyldioxirane in acetone (Boyd at al., J. Chem. Soc., Perkin    Trans. 1991, 2, 2189).

In addition, specific methods for preparing diaryl ureas andintermediate compounds are already described elsewhere in the patentliterature, and can be adapted to the compounds of the presentinvention. For example, Miller S. at al, “Inhibition of p38 Kinase usingSymmetrical and Unsymmetrical Diphenyl Ureas” PCT Int. Appl. WO 9932463, Miller, S et al. “Inhibition of raf Kinase using Symmetrical andUnsymmetrical Substituted Diphenyl Ureas” PCT Int. Appl., WO 99 32436,Dumas, J. et al., “Inhibition of p38 Kinase Activity using SubstitutedHeterocyclic Ureas” PCT Int. Appt, WO 99 32111, Dumas, J. et al.,“Method for the Treatment of Neoplasm by Inhibition of raf Kinase usingN-Heteroaryl-N′-(hetero)arylureas” PCT Mt. Appl., WO 99 32106, Dumas, J.at al., “Inhibition of p38 Kinase Activity using Aryl- andHeteroaryl-Substituted Heterocyclic Ureas” PCT Int. Appl., WO 99 32110,Dumas, J., et al., “Inhibition of raf Kinase using Aryl- andHeteroaryl-Substituted Heterocyclic Ureas” PCT Int. Appl., WO 99 32455,Riedl, B., at al., “O-Carboxy Aryl Substituted Diphenyl Ureas as rafKinase Inhibitors” PCT Int. Appl., WO 00 42012, Riedl, B., et al.,“O-Carboxy Aryl Substituted Diphenyl Ureas as p38 Kinase Inhibitors” PCTInt. Appl.; WO 00 41698, Dumas, J. et al. “Heteroaryl ureas containingnitrogen hetero-atoms as p38 kinase inhibitors” U.S. Pat. Appl. Publ.,US 20020065296, Dumas, J. et. al. “Preparation ofN-aryl-N′-[(acylphenoxy)phenyl]ureas as raf kinase inhibitors” PCT Int.Appl., WO 02 62763, Dumas, J. at al. “Inhibition of raf kinase usingquinolyl, isoquinolyl or pyridyl ureas” PCT Int. Appl., WO 02 85857,Dumas, 3. et al. “Preparation of quinolyl, isoquinolyl or pyridyl-ureasas inhibitors of raf kinase for the treatment of tumors and/or cancerouscell growth” U.S. Pat. Appl. Publ., US 20020165394. All the precedingpatent applications are hereby incorporated by reference.

Synthetic transformations that may be employed in the synthesis ofcompounds of formula (I) and in the synthesis of intermediates involvedin the synthesis of compounds of formula (I) are known by or accessibleto one skilled in the art. Collections of synthetic transformations maybe found in compilations, such as:

-   J. March. Advanced Organic Chemistry, 4^(th) ed.; John Wiley: New    York (1992);-   R. C. Larock. Comprehensive Organic Transformations, 2^(nd) ed.;    Wiley-VCH: New York (1999);-   F. A. Carey; R. J. Sundberg. Advanced Organic Chemistry, 2^(nd) ed.;    Plenum Press: New York (1984);-   T. W. Greene; P. G. M. Wuts. Protective Groups in Organic Synthesis,    3^(rd) ed.; John Wiley: New York (1999);-   L. S. Hegedus. Transition Metals in the Synthesis of Complex Organic    Molecules, 2^(nd) ed.; University Science Books: Mill Valley, Calif.    (1994);-   L. A. Paquette, Ed. The Encyclopedia of Reagents for Organic    Synthesis; John Wiley: New York (1994);-   A. R. Katritzky; O. Meth-Cohn; C. W. Rees, Eds. Comprehensive    Organic Functional Group Transformations; Pergamon Press: Oxford,    UK. (1995);-   G. Wilkinson; F. G A. Stone; E.W. Abel, Eds. Comprehensive    Organometallic Chemistry; Pergamon Press: Oxford, UK (1982);-   B. M. Trost; I. Fleming. Comprehensive Organic Synthesis; Pergamon    Press: Oxford, UK (1991);-   A. R. Katritzky; C. W. Rees Eds. Comprehensive Heterocylic    Chemistry; Pergamon Press: Oxford, UK (1984);-   A. R. Katritzky; C. W. Rees; E. F. V. Scriven, Eds. Comprehensive    Heterocylic Chemistry II; Pergamon Press: Oxford, UK (1996); and-   C. Hansch; P. G. Semmes; T. H. Taylor, Eds. Comprehensive Medicinal    Chemistry; Pergamon Press: Oxford, UK (1990).

In addition, recurring reviews of synthetic methodology and relatedtopics include Organic Reactions; John Wiley: New York; OrganicSyntheses; John Wiley: New York; Reagents for Organic Synthesis; JohnWiley: New York; The Total Synthesis of Natural Products; John Wiley:New York; The Organic Chemistry of Drug Synthesis; John Wiley: New York;Annual Reports in Organic Synthesis; Academic Press: San Diego Calif.;and Methoden der Organischen Chemie (Houben-Weyl); Thieme: Stuttgart,Germany. Furthermore, databases of synthetic transformations includeChemical Abstracts, which may be searched using either CAS OnLine orSeiFinder, Handbuch der Organischen Chemie (Beilstein), which may besearched using SpotFire, and REACCS.

Further Therapeutic Agents

The compounds of formula I according to the present invention can becombined with further therapeutic agents such as anti-viral agents,corticosteroids, immunomodulatory agents and/or known drugs for thetherapy of SARS coronavirus infections and/or SARS itself.

Examples of anti-viral agents include, but are not limited to, e.g.ribavirin, lopinavir, ritonavir, the combination of lopinavir andritonavir (Kaletra), AG 7088, hexapeptidyl CMK, interferon-β, interferonalfacon-1, interferon-α and pegylated interferon-α. Preference asfurther therapeutic agent is given to lopinavir and/or ritonavir.

Examples of corticosteroids include, but are not limited to, e.g.aldosteron, hydrocortisone, dexamethasone, prednisolone,methylprednisolone and cortisol.

Examples of immunomodulatory agents include, but are not limited to, e.gimmunoglobulin, convalescent plasma, interferon-β, interferon alfacon-1,interferon-α and pegylated interferon-α.

The compounds of formula I according to the present invention can becombined with further therapeutic agents such as antiviral,antiretroviral agents, immunomodulatory agents and/or known drugs forthe therapy of HIV infections and/or diseases caused by HIV infections.

Examples of antiviral or antiretroviral agents include, but are notlimited to, e.g. lamivudin (3TC), abacavir, tenofovir disproxil fumarat,emtricitabine, didanosine, stavudine, zidovudine, zalcitabine,efavirenz, nivirapine, delaviridine, atazanavir, ritonavir, amprenavir,lopinavir, rironavir, nelfinavir, indinavir, saquinavir, enfuvirtide,etravirine, capravirine and tenofovir. Preference is given to indinavir,zidovudine, tenofovir, parapoxvirus ovis and lamivudin.

Examples of immunomodulatory agents include, but are not limited to,e.g. parapoxvirus ovis.

The compounds of formula I according to the present invention can becombined with further therapeutic agents such as anti-viral agentsand/or immunomodulatory agents.

Examples of anti-viral agents include, but are not limited to, e.g.lamivudin (3TC), ribavirin, adevovir, adevovir dipivoxil, entecavir,emtricitabine, devudine, L-dT, L-Fd4C, interferon-a and pegylatedinterferon-α. Preference as further therapeutic agent is given tolamivudin and/or adevovir dipivoxil.

Examples of immunomodulatory agents include, but are not limited to,e.g. parapoxvirus ovis, CpG-oligonucleotide, thymosin-α, interferon-αand pegylated interferon-α. Preference as immunomodulatory agent isgiven to pegylated interferon-α.

The compounds of formula I according to the present invention can becombined with further therapeutic agents such as anti-viral agentsand/or immunomodulatory agents.

Examples of anti-viral agents include, but are not limited to, e.g.arnantidin, symmetrel, flumadine, oseltamvir and zanamivir. Preferenceis given to oseltamvir and zanamivir.

Examples of immunomodulatory agents include, but are not limited to,e.g. parapoxvirus ovis, interferon-β, interferon affacon-1, interferon-αand pegylated interferon-α. Preference as immunomodulatory agent isgiven to pegylated interferon-α.

The compounds of formula I according to the present invention can becombined with further therapeutic agents such as antiviral agents,immunomodulatory agents (e.g. immunoglobulins), antiviral antibodies,inhibitors of the helikase-primase complex and/or known drugs for thetherapy of Herpesviridae viruses infections and/or diseases caused byHerpesviridae viruses infections.

Examples of antiviral agents include, but are not limited to, e.g.acyclovir; valacyclovir, peniciclovir, famicilovir, foscarnet, brivudin,ganciclovir and cidofovir. Preference is given to acyclovir.

The compounds of formula I according to the present invention can becombined with further therapeutic agents such as antiviral agents,immunomodulatory agents, vaccines and/or known drugs for the therapy ofPapovaviridae viruses infections and/or diseases caused by Papovaviridaeviruses infections.

Examples of further therapeutic agents include, but are not limited to,e.g. interferon, imiquimod, resiquimod, podophyllin, bleomycin andretinoid.

Furthermore compounds and combinations of the present invention can beused in combination with a laser therapy, a photodynamic therapy or athermo-cauterization.

The compounds of formula I according to the present invention can becombined with further therapeutic agents such as antiviral agents,immunomodulatory agents and/or known drugs for the therapy of virusesinfections according to the invention and/or diseases caused by suchvirus infections.

Examples of antiviral and/or immunomodulatory agents include, but arenot limited to, e.g. interferon-β, interferon alfacon-1, interferon-α orpegylated interferon-α.

The compounds of formula I according to the present invention can becombined with further therapeutic agents such as antiviral agents,corticosteroids, immunomodulatory agents and/or known drugs for thetherapy of Poxyiridae viruses infections and/or diseases caused byPoxyiridae viruses infections.

Examples of antiviral and/or immunomodulatory agents include, but arenot limited to, e.g. cidofovir, interferon-β, interferon alfacon-1,interferon-α or pegylated interferon-α.

The compounds of formula I according to the present invention can becombined with further therapeutic agents such as antiviral agents,corticosteroids, immunomodulatory agents and/or known drugs for thetherapy of Flaviviridae viruses infections and/or diseases caused byFlaviviridae viruses infections.

Examples of antiviral and/or immunomodulatory agents include, but arenot limited to, e.g. ribavirin, interferon-β, interferon alfacon-1,interferon-cc or pegylated interferon-α.

The compounds of formula I according to the present invention can becombined with further therapeutic agents such as antiviral agents,immunomodulatory agents and/or known drugs for the therapy ofPicornaviridae viruses infections and/or diseases caused byPicornaviridae viruses infections.

Examples of antiviral agents include, but are not limited to, e.g.ruprintrivir (AG 7088), 3C protease inhibitors, pirodavir, pleconariland soluble ICAM-1. Preference is given to ruprintrivir and pirodavir.

Examples of immunomodulatory agents include, but are not limited to,e.g. parapoxvirus ovis, interferon-β, interferon alfacon-1, interferon-αor pegylated interferon-α. Preference is given to parapoxvirus ovis andpegylated interferon-α.

Indications

The compounds and combinations according to the present invention can beused for manufacture of a medicament for treating SARS-CoV infectionsand/or SARS itself. Also the present invention provides methods oftreating SARS-CoV infections and/or SARS itself comprising administeringeffective amounts of at least one compound of formula I and optionallyat least one further therapeutic agent according to the invention. An“effective amount” is the quantity of the compound that is useful toachieve the desired result, e.g., to treat the disease or condition. Anysubject can be treated in accordance with the present invention,including, e.g., invertebrates, vertebrates, mammals (e.g., humans;non-human primates; monkeys; livestock, such as cows, pigs, and sheep;dogs; cats; rodents; rats; mice), and birds (e.g., chicken; turkey; andducks).

Treatment of the virus infections and diseases caused or associated withsuch infections according to the invention include not only thetreatment of subjects who are infected by the virus, but also thetreatment of subjects in which the infection or disease has not yetappeared, become symptomatic, or erupted. The present invention furtherrelates to preventing or reducing recurring eruptions or attacksassociated with viral infection. The term “treating” is usedconventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving, etc.,one or more symptoms of the viral infection or associated disease.Furthermore compounds and combinations according to the inventioninhibit replication of SARS-CoV and show further positive therapeuticeffects. Also compounds and combinations according to the presentinvention can be used for treating SARS infections with coronaviruslines which are resistant to standard therapies.

Any symptom of SARS-CoV can be treated in accordance with the presentinvention, including e.g., fever (>38° C.), headache, dry cough,pneumonia, and/or respiratory distress.

All SARS-CoV variants can be treated in accordance with the presentinvention, including, but not limited to, e.g., TOR2 (AY274119); Urbani(AY278741); CUHK-W1 (AY278554); CUHK-Su10 (AY282752); HKU-39849(AY278491); SIN2500 (AY283794); SIN2677 (AY283795); SIN2679 (AY283796);SIN2748 (AY283797); SIN2774 (AY283798); TW1 (AY291451); BJ01 (AY278488);BJ02 (AY278487); 13303 (AY278490); BJ04 (AY279354); GZ01 (AY278489); andsequence variations and mutations of SARS-CoV, including those whichincrease the pathogenicity and/or transmission modes. See, also,Pavlovic-Lazetic et al., BMC Bioinformatics 2004, 5:65, e.g., Table 1;Zhao et al., BMC Evolutionary Biology 2004:21; Yeh et al., Proc. Natl.Acad. Sci., 101:2542, 2004. For example, mutations in the Spike genehave been suggested as essential for the transition from animal-to-humantransmission. See, e.g., Song et al., Proc. Natl. Acad. Sci, 102:2430,2005.

The compounds and combinations according to the present invention can beused for manufacture of a medicament for treating HIV infections and/ordiseases caused by HIV infections. Also the present invention providesmethods of treating HIV infections and/or diseases caused by HIV.infections comprising administering effective amounts of at least onecompound of formula I and optionally at least one further therapeuticagent according to the invention. An “effective amount” is the quantityof the compound that is useful to achieve the desired result, e.g., totreat the disease or condition. Any subject can be treated in accordancewith the present invention, including, e.g., invertebrates, vertebrates,mammals (e.g., humans; non-human primates; monkeys; livestock, such ascows, pigs, and sheep; dogs; cats; rodents; rats; mice), and birds(e.g., chicken; turkey; and ducks).

Any strain, subtype, etc., of HIV can be treated in accordance with thepresent invention, including viruses related to HIV. These include, butare not limited to, e.g., HIV-I (e.g., clades A, B, C, D, F, G, R5 andR5X4 viruses, including recombinants thereof, such as A/D, etc.), HIV-2(e.g., R5 and R5X4 viruses, etc.), simian immunodeficiency virus (Sly),simian/human immunodeficiency virus (SHIV), feline immunodeficiencyvirus (FIV), bovine immunodeficiency virus (BIV) (Wright et al., Vet.Res. Commun., 26:239-50, 2002), HTLV-1, HTLV-2, etc. Phylogeneticanalysis has classified HIV-1 into three groups: the major (M) group,the outlier (O) group, and the non-M, non-O (N) group. Group M isresponsible for the majority of HIV infections. The other two groups arehighly diverse and less prevalent. Group M isolates can be subdividedinto nine subtypes (A to D, F to H, J, and K) and a number ofcirculating recombinant forms (CRFs), which have identical mosaicgenomes and are assumed to have arisen by recombination betweendifferent subtypes. In HIV-2, only types A and B have been found in anysignificant number of people. See, e.g., Robertson et al., Science,2000, 288, 55; HIV database at the worldwide web (www) addresshiv.lanl.gov.

Treatment of the virus infections and diseases caused or associated withsuch infections according to the invention include not only thetreatment of subjects who are infected by the virus, but also thetreatment of subjects in which the infection or disease has not yetappeared, or become symptomatic. For example, subjects can be treatedwho have tested positive for HIV virus (e.g., using PCR, RT-PCR., etc.),HIV antibody (e.g., gp120, gp41, gp120/160, p24, etc., antibodies), orHIV antigens, but have not manifested the disease (e.g., decling CD4T-cell counts are considered to be a marker of the progression of HIVinfection; AIDS, e.g., when the count drops below 200 cells per cubicmillimeter, or when opportunistic infections occur). Subjects can alsobe selected for treatment with a compound of the present invention whoare specific stages of the disease, e.g., having AIDS; experiencingimmune collapse; having levels of CD4 T-cells below a specified value,e.g., below about 200 cells, below about 500 cells; having levels ofviral load above a specified value, e.g., greater than about 5,000copies HIV RNA per ml plasma, greater than about 5,000 copies HIV RNAper ml plasma, greater than about 5,000 copies HIV RNA per ml plasma,etc.

The present invention further relates to preventing or reducing symptomsassociated with viral infection. These include symptoms associated withthe minor symptomatic phase of HIV infection, including, e.g., shingles;skin rash and nail infection; mouth sores; recurrent nose and throatinfection; and weight loss. In addition, further symptoms of associatedwith the major symptomatic phase of HIV infection, include, e.g., oraland vaginal thrush (Candida); persistent diarrhoea; weight loss;persistant cough and reactivated tuberculosis; recurrent herpesinfections such as cold sores (herpes simplex), Symptoms of full-blownAIDS which can be treated in accordance with the present invention,include, e.g., diarrhoea, nausea and vomiting; thrush and mouth sores;persistent, recurrent vaginal infections and cervical cancer; persistentgeneralised lymphadenopathy (PGL); severe skin infections, warts andringworm; respiratory infections; pneumonia, especially pneumocystiscarinii pneumonia (PCP); herpes zoster (or shingles); nervous systemproblems, such as pains, numbness or “pins and needles” in the hands andfeet; neurological abnormalities; Kaposi's sarcoma; lymphoma;tuberculosis, e.g., the occurrence of opportunistic infections; Karposi.The term “treating” is used conventionally, e.g., the management or careof a subject for the purpose of combating, alleviating, reducing,relieving, improving, etc., one or more symptoms of the viral infectionor associated disease.

Furthermore compounds and combinations according to the inventioninhibit replication of HIV and show further positive therapeuticeffects. Also compounds and combinations according to the presentinvention can be used for treating HIV infections with virus lines whichare resistant to standard therapies.

Examples of diseases caused by HIV infections include, but are notlimited to, e.g. AIDS (acquired immunodeficiency syndrome) and Kaposi'ssyndrome.

The compounds and combinations according to the present invention can beused for manufacture of a medicament for treating hepatitis virusinfections and/or diseases caused by hepatitis virus infections. Alsothe present invention provides methods of treating hepatitis virusinfections and/or diseases caused by hepatitis virus infectionscomprising administering effective amounts of at least one compound offormula I and optionally at least one further therapeutic agentaccording to the invention. An “effective amount” is the quantity of thecompound that is useful to achieve the desired result, e.g., to treatthe disease or condition. Any subject can be treated in accordance withthe present invention, including, e.g., invertebrates, vertebrates,mammals (e.g., humans; non-human primates; monkeys; livestock, such ascows, pigs, and sheep; dogs; cats; rodents; rats; mice), and birds(e.g., chicken; turkey; and ducks).

Treatment of the virus infections and diseases caused or associated withsuch infections according to the invention include not only thetreatment of subjects who are infected by the virus, but also thetreatment of subjects in which the infection or disease has not yetappeared or become symptomatic. The present invention further relates topreventing or reducing recurring attacks associated with viralinfection. The term “treating” is used conventionally, e.g., themanagement or care of a subject for the purpose of combating,alleviating, reducing, relieving, improving, etc., one or more symptomsof the viral infection or associated disease.

Furthermore compounds and combinations according to the inventioninhibit replication of hepatitis virus infections and show furtherpositive therapeutic effects. Also compounds and combinations accordingto the invention can be used for treating infections with hepatitisvirus lines which are resistant to standard therapies.

Examples of hepatitis virus infections include, but are not limited to,e.g. infections with hepatitis A virus (HAV), hepatitis B virus (HBV),hepatitis C virus (HCV), hepatitis D virus (HDV), hepatitis E virus(HEV) and hepatitis G virus (HGV). Preference is given to infectionswith human hepatitis virus. More preferably HCV and/or HBV infectionsare mentioned.

Any type, strain, or species of hepatitis can be treated in accordancewith the present invention, including all mammalian strains, e.g.,human, porcine, etc. The main HCV genotypes include types 1, 2, 3, 4, 5,6, 7, 8, 9, 10, and 11. These can be further classified into: 1a, 1b,1c, 2a, 2b, 2c, 3a, 3b, 4a-4-e, 5a, 6a, 7a, 7b, 8a, 8b, 9a, 10a, and11a. See, also, e.g., Stuyver et al. (1993), Typing of hepatitis C virus(HCV) isolates and characterization of new (sub)types using a Line ProbeAssay. J Gen Virology, 74: 1093-1102; Stuyver et al. (1996),Second-generation line probe assay for hepatitis C virus genotyping. J.Clin. Microbiol. 34, 2259-2266; U.S. Patent Application Nos.20050069870. REV can be classified into seven strains, e.g., A-H. See,also, Miyakawa and Mizokami, Intervirology, 2003; 46(6):329-38. isolatesof HEV have been classified by genomic analysis into at least types 1,2, 3, and 4.

Examples of diseases caused by hepatitis virus infection include, butare not limited to, e.g. hepatitis, cirrhosis and cancer of the liver,jaundice, chronically infection of the liver and associated diseases andmodifications of the liver thereof.

The compounds and combinations according to the present invention can beused for manufacture of a medicament for treating influenza virusinfections and/or diseases caused by influenza virus infections. Alsothe present invention provides methods of treating influenza virusinfections and/or diseases caused by influenza virus infectionscomprising administering effective amounts of at least one compound offormula I and optionally at least one further therapeutic agentaccording to the invention. An “effective amount” is the quantity of thecompound that is useful to achieve the desired result, e.g., to treatthe disease or condition. Any subject can be treated in accordance withthe present invention, including, e.g., invertebrates, vertebrates,mammals (e.g., humans; non-human primates; monkeys; livestock, such ascows, pigs, and sheep; dogs; cats; rodents; rats; mice), and birds(e.g., chicken; turkey; and ducks).

Treatment of the virus infections and diseases caused or associated withsuch infections according to the invention include not only thetreatment of subjects who are infected by the virus, but also thetreatment of subjects in which the infection or disease has not yetappeared, become symptomatic, or erupted. The present invention furtherrelates to preventing or reducing recurring eruptions or attacksassociated with viral infection. The term “treating” is usedconventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving, etc.,one or more symptoms of the viral infection or associated disease.

Furthermore compounds and combinations according to the inventioninhibit replication of influenza virus infections and show furtherpositive therapeutic effects. Also compounds and combinations accordingto the invention can be used for treating infections with influenzavirus lines which are resistant to standard therapies.

Examples of influenza virus infections include, but are not limited to,e.g. infections with orthomyxoviruses, influenza A virus, influenza Bvirus and influenza C virus.

Examples of influenza viral infections that can be treated in accordancewith the present invention include, e.g., influenza virus A (includingall strains varying in their HA and NA proteins, such as H1N1, H1N2, andH3N2; H7N7; H3N8); influenza B, influenza C, thogoto virus (includingDhori, Balken virus, SiAR 126 virus), and isavirus (e.g., infectioussalmon anemia virus). These include influenza isolated or transmittedfrom all species types, including isolates from invertebrates,vertebrates, mammals, humans, non-human primates, monkeys, pigs, cows,and other livestock, birds, domestic poultry such as turkeys, chickens,quail, and ducks, wild birds (including aquatic and terrestrial birds),reptiles, etc. These also include existing strains which have changed,e.g., through mutation, antigenic drift, antigenic shift, recombination,etc., especially strains which have increased virulence and/orinterspecies transmission (e.g., human-to-human).

Of particular interest are influenza viruses which are panzootic and/orwhich cross species either because they have a broad host range, byrecombination in the infected host, and/or mutation. For example, H5N1(in reference to the subtypes of surface antigens present on the virus,hemagglutinin type 5 and neuraminadase type 1) is a subtype of avianinfluenza A, which caused an outbreak of flu in domestic birds in Asia.As of November 2005, more 120 million birds died from infection or werekilled to prevent thriller infection from spreading. This virus has alsospread into human hosts (“bird flu”) where it is associated with highlethality.

Avian influenza A virus strains can be classified as low pathogenic(LPAI) or highly pathogenic (HPAI) on the basis of specific moleculargenetic and pathogenesis criteria that require specific testing. Mostavian influenza A viruses are LPAI viruses that are usually associatedwith mild disease in poultry. In contrast, HPAI viruses can cause severeillness and high mortality in poultry. More recently, some HPAI viruses(e.g., H5N1) have been found to cause no illness in some poultry, suchas ducks. LPAI viruses have the potential to evolve into HPAI virusesand this has been documented in some poultry outbreaks. Avian influenzaA viruses of the subtypes H5 and H7, including H5N1, H7N7, and H7N3viruses, have been associated with HPAI, and human infection with theseviruses have ranged from mild (H7N3, H7N7) to severe and fatal disease(H7N7, H5N1). Human illness due to infection with LPAI viruses has beendocumented, including very mild symptoms (e.g., conjunctivitis) toinfluenza-like illness. Examples of LPAI viruses that have infectedhumans include H7N7, H9N2, and H7N2. Compounds of the present inventioncan be utilized to treat infections associated with such viruses.

Influenza A H5

At least nine subtypes of H5 have been identified. H5 infections, suchas HPAI H5N1 viruses currently circulating in Asia and Europe, have beendocumented among humans and can cause severe illness or death.

Influenza A H7

At least nine subtypes of H7 have been identified. H7 infection inhumans is rare but can occur among persons who have direct contact withinfected birds. Symptoms may include conjunctivitis and/or upperrespiratory symptoms. H7 viruses have been associated with both LPAI(e.g., H7N2, H7N7) and HPAI (e.g., H7N3, H7N7), and have caused mild tosevere and fatal illness in humans. The H subtypes are epidemiologicallymost important, as they govern the ability of the virus to bind to andenter cells, where multiplication of the virus then occurs. The Nsubtypes govern the release of newly formed virus from the cells

Influenza A H9

At least nine subtypes of H9 have been identified. Influenza A H9 hasrarely been reported to infect humans. However there are reports ofchildren exhibiting flu-like syndromes when infected with H9 strains.See, e.g., Anonymous. Influenza: Hong Kong Special Administrative Regionof China. W H O Weekly Epidemiol Rec. 1999; 14:111. The presentinvention relates to the treatment of all avian influenza subtypes(e.g., H and N subtypes), including existing subtypes, derivativesthereof, and recombinants thereof, such as subtypes and recombinantswhich have the ability to spread from human-to-human. Various isolateshave been characterized, especially for H5 subtypes. See, e.g.,Sturm-Ramirez, J. Virol., 2004, 78, 4892-4901; Guan et al., Proc. Natl.Acad. Sci., 2004, 101, 8156-8161.

Influenza subtyping can be accomplished routinely, e.g., using PCR ongenomic sequences. See, also Kessler et al., J. Clin. Microbial., 2004,42, 2173-2185.

Examples of diseases caused by influenza virus infection include, butare not limited to, e.g. flu, bird flu, swine flu, etc.

Compounds of the present invention can treat one or more symptomsassociated with influenza infection, including, e.g., fever, cough, sorethroat, sore muscles, pneumonia, respiratory failure, acute respiratorydistress syndrome, conjunctivitis, and toxic-shock-like syndrome (e.g.,fever, chills, vomiting, and headache). Compounds of the presentinvention can also reduce, block, lessen, decrease, etc., the productionof cytokines associated with influenza infection, e.g., reducing theoccurrence of hypereytokinemia (“cytokine storm”) and the symptomsassociated with over-expression of cytokines.

The compounds and combinations according to the present invention can beused for manufacture of a medicament for treating Herpesviridae virusesinfections and/or diseases caused by such infections. Also the presentinvention provides methods of treating Herpesviridae viruses infectionsand/or diseases caused by such infections comprising administeringeffective amounts of at least one compound of formula I and optionallyat least one further therapeutic agent according to the invention. An“effective amount” is the quantity of the compound that is useful toachieve the desired result, e.g., to treat the disease or condition. Anysubject can be treated in accordance with the present invention,including, e.g., mammals (e.g., humans; non-human primates; monkeys;livestock, such as cows, pigs, and sheep; dogs; cats; rodents; rats;mice), and birds (e.g., chicken; turkey; and ducks). See, also any ofthe subjects listed in Table 1.

Treatment of the virus infections and diseases caused or associated withsuch infections according to the invention include not only thetreatment of subjects who are infected by the virus, but also thetreatment of subjects in which the infection or disease has not yetappeared, become symptomatic, or erupted. The present invention furtherrelates to preventing or reducing recurring eruptions or attacksassociated with viral infection. The term “treating” is usedconventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving, etc.,one or more symptoms of the viral infection or associated disease.

Furthermore compounds and combinations according to the inventioninhibit replication of Herpesviridae viruses and show further positivetherapeutic effects. Also compounds and combinations according to thepresent invention can be used for treating Herpesviridae virusesinfections with virus lines which are resistant to standard therapies.

The virus family Herpesviridae include Alphaherpesviridae,Betaherpesviridae and Gamma-herpesviridae. Examples of Herpesviridaeviruses include, but are not limited to, simplexviruses such as humanherpes simplex viruses, varicelloviruses such as human varizella zostervirus, cytomegalovirus, roseolovirus, Epstein-Barr virus, equineviruses, Aujeszky's virus, suid virus, apish herpesviruses,cercophitecinem herpesviruses, ateline herpesvirus, bovineherpesviruses, feline herpesvirus and canine herpesvirus.

Examples of diseases caused by Herpesviridae viruses infections include,but are not limited to, e.g. infections of the lymphatic system of theouter genitalia, the lips (including oral herpes), the brain(herpesencephalitis) or the peripheral nerves. Other diseases andassociated viruses include, e.g., cold or fever sores (e.g., herpessimplex 1), genital herpes (e.g., herpes simplex 2), chickenpox(varicella-zoster virus), shingles (varicella-zoster virus), infectiousmononucleosis (Epstein-Barr virus), roseola (e.g., HHV-6a and HHV-7),gingival stomatitis, herpes genitalis, herpes labialis, herpesgladiatorum, encephalitis, keratoconjunctivitis, Karposi's sarcoma(herpesvirus 8), etc. Any infection or diseases associated withHerpesviridae can be treated in accordance with the present invention,including those mentioned in Table 1.

The compounds and combinations according to the present invention can beused for manufacture of a medicament for treating Papovaviridae virusesinfections and/or diseases caused by such infections. Also the presentinvention provides methods of treating Papovaviridae viruses infectionsand/or diseases caused by such infections comprising administeringeffective amounts of at least one compound of formula I and optionallyat least one further therapeutic agent according to the invention. An“effective amount” is the quantity of the compound that is useful toachieve the desired result, e.g., to treat the disease or condition. Anysubject can be treated in accordance with the present invention,including, e.g., invertebrates, vertebrates, mammals (e.g., humans;non-human primates; monkeys; livestock, such as cows, pigs, and sheep;dogs; cats; rodents; rats; mice), and birds (e.g., chicken; turkey; andducks). See, also any of the subjects listed in Table 1.

Treatment of the virus infections and diseases caused or associated withsuch infections according to the invention include not only thetreatment of subjects who are infected by the virus, but also thetreatment of subjects in which the infection or disease has not yetappeared, become symptomatic, or erupted. The present invention furtherrelates to preventing or reducing recurring eruptions or attacksassociated with viral infection. The term “treating” is usedconventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving, etc.,one or more symptoms of the viral infection orassociated disease.

Furthermore compounds and combinations according to the inventioninhibit replication of Papovaviridae viruses and show further positivetherapeutic effects. Also compounds and combinations according to thepresent invention can be used for treating Papovaviridae virusesinfections with virus lines which are resistant to standard therapies.

The virus family Papovaviridae include, but is not limited to, e.g.papillomaviruses such as the human papillomaviruses (HPV 6, 11, 16, 18).

Examples of diseases caused by Papovaviridae viruses infections include,but are not limited to, e.g. papillomas, warts such as anogenital wartsand neoplasm of the dermis caused by such infections.

Any Papovaviridae infection can be treated, including those listed inTable 2, and especially paillomaviral infections, such as the HPV typesand diseases listed in Table 3. Subjects harbouring HPV viruses can betreated in accordance with the present invention, including subjectswith asymptomatic infection, classical condylomata (genital warts), andsubclinical infection (e.g., lesions not visible on routine inspection).HPV typing can be conducted routinely. See, e.g., Roman and Fife,Clinical Microb. Rev., 2:166-190, 1989.

There are two polyomaviruses found in humans: JC virus, which can infectthe respiratory system, kidneys, or brain (e.g., causing the fatalprogressive multifocal leukoencephalopathy), and BK virus, whichproduces a mild respiratory infection and can affect the kidneys ofimmunosuppressed transplant patients. An avian polyomavirus, referred toas the Budgerigar fledgling disease virus, is a frequent cause of deathamong caged birds. Any of these viruses and associated diseases can betreated in accordance with the present invention.

The compounds and combinations according to the present invention can beused for manufacture of a medicament for treating virus infectionsaccording to the present invention and/or diseases caused by suchinfections. Also the present invention provides methods of treatingvirus infections according to the present invention and/or diseasescaused by such infections comprising administering effective amounts ofat least one compound of formula I and optionally at least one furthertherapeutic agent according to the invention. An “effective amount” isthe quantity of the compound that is useful to achieve the desiredresult, e.g., to treat the disease or condition. Any subject can betreated in accordance with the present invention, including, e.g.,invertebrates, vertebrates, mammals (e.g., humans; non-human primates;monkeys; livestock, such as cows, pigs, and sheep; dogs; cats; rodents;rats; mice), and birds (e.g., chicken; turkey; and ducks).

Treatment of the virus infections and diseases caused or associated withsuch infections according to the invention include not only thetreatment of subjects who are infected by the virus, but also thetreatment of subjects in which the infection or disease has not yetappeared or become symptomatic. The present invention further relates topreventing or reducing recurring eruptions or attacks associated withviral infection. The term “treating” is used conventionally; e.g., themanagement or care of a subject for the purpose of combating,alleviating, reducing, relieving, improving, etc., one or more symptomsof the viral infection or associated disease.

Furthermore compounds and combinations according to the inventioninhibit replication of viruses according to the present invention andshow further positive therapeutic effects. Also compounds andcombinations according to the present invention can be used for treatingvirus infections according to the present invention with virus lineswhich are resistant to standard therapies.

Examples of viruses according to the present invention are viruses ofthe family Reoviridae such as human rotavirus, of the familyAstroviridae such as astrovirus, of the family Bunyaviridae such asbunyamweravirus, California encephalitis virus, Hantaan virus, LaCrossevirus, Muerto Canyon virus, Rift Valley Fever virus, sandfly fever virusor tahyna virus, of the family Filoviridae such as ebola virus orMarburg virus, of the family Arenaviridae such as Junin virus, Lassavirus, lymphotropic choriomeningitis virus or Machupo virus, of thefamily Rhabdoviridae such as hydrophobia virus, Duvenhage virus, Mokolavirus or vesicular stomatitis virus, of the family Togaviridae such asChikungunya virus, Eastern Equine Encephalitis virus, Mayaro virus,O'nyong-nyong virus, ross fever virus, roseola virus or other EquineEncephalitis viruses, of the family Paramyxoviridae such as measlesvirus, mumps virus or parainfluenza virus and unclassified prions suchas prions causing Jakob-Creutzfeld disease, BSE or Kuru and itsdifferent variants; family Parvoviridae, such as erythrovirus (e.g., B19virus) and dependovirus (e.g., adeno-associated virus, AAV-2); familyAdenoviridae, such as Mastadenovirus (e.g., human adenovirus serotypes1047).

The compounds and combinations according to the present invention can beused for manufacture of a medicament for treating Poxyiridae virusesinfections and/or diseases caused by such infections. Also the presentinvention provides methods of treating Poxyiridae viruses infectionsand/or diseases caused by such infections comprising administeringeffective amounts of at least one compound of formula I and optionallyat least one further therapeutic agent according to the invention. An“effective amount” is the quantity of the compound that is useful toachieve the desired result, e.g., to treat the disease or condition. Anysubject can be treated in accordance with the present invention,including, e.g., mammals (e.g., humans; non-human primates; monkeys;livestock, such as cows, pigs, and sheep; dogs; cats; rodents; rats;mice), and birds (e.g., chicken; turkey; and ducks). See, also any ofthe subjects listed in Table 4.

Treatment of the virus infections and diseases caused or associated withsuch infections according to the invention include not only thetreatment of subjects who are infected by the virus, but also thetreatment of subjects in which the infection or disease has not yetappeared, become symptomatic, or erupted. The present invention furtherrelates to preventing or reducing recurring eruptions or attacksassociated with viral infection. The term “treating” is usedconventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving, etc.,one or more symptoms of the viral infection or associated disease. Forexample, about 7-17 days after exposure to variola virus, an infectedsubject can begin to experience the first symptoms of smallpox disease.A compound administered during this time period, or at any point duringthe disease, can prevent or inhibit progression of the disease. Thecompounds can block, reduce, diminish, alleviate, etc., one or moresymptoms of the disease, including, but not limited to, e.g., fever,malaise, head and body aches, vomiting, prodrome phase, typical oratypical rash during all its phases, hemorrhagic rash, hemorrhage, etc.These compounds can reduce the severity of the disease, as well as thedegree and period during which it is contagious.

Adverse reactions and other effects of poxvirus vaccination can also betreated in accordance with the present invention, e.g., by administeringan effective amount of a compound of the present invention. Adversereactions to vaccinia vaccination include, but are not limited to, e.g.,generalized vaccinia, progressive vaccinia, eczema vaccinatum,post-vaccinal encephalitis, vaccinial myocarditis and/or pericarditis,ocular vaccinia, encephalomyelitis (PVEM), fetal vaccinia, etc.Furthermore compounds and combinations according to the inventioninhibit replication of Poxyiridae viruses and show further positivetherapeutic effects. Also compounds and combinations according to thepresent invention can be used for treating Poxyiridae viruses infectionswith virus lines which are resistant to standard therapies.

Any poxvirus infection can be treated and/or prevented in accordancewith the present invention, including, but not limited to, infectionsand diseases associated with orthopoxvirus, parapoxvirus, avipovirus,capripoxvirus, leporipoxvirus, suipoxvirus, molluscum contagiosum virusfowlpox, etc. Orthopoxvirus, include, e.g., buffalopox, camelpox,cowpox, monkeypox, rabbitpox, raccoon pox, tatera pox, canarypox,vaccinia, variola (smallpox), and vole pox. For other poxvirus, seee.g., Virology, Fields et al., Volume 2, Chapters 74-75, Raven Press,1990.

Diseases that can be treated in accordance with the present inventioninclude, e.g, smallpox (variola virus); cowpox (cowpox virus);contagious pustular dermatitis (orf virus); pseudocowpox(pseudocowpoxvirus); molluscum contagiousum (molluscum contagiosumvirus); histocytomaa of head or limbs (Yaba monkey tumor virus); tanapox(tanapox virus), etc.

The compounds and combinations according to the present invention can beused for manufacture of a medicament for treating Flaviviridae virusesinfections and/or diseases caused by such infections. Also the presentinvention provides methods of treating Flaviviridae viruses infectionsand/or diseases caused by such infections comprising administeringeffective amounts of at least one compound of formula I and optionallyat least one further therapeutic agent according to the invention. An“effective amount” is the quantity of the compound that is useful toachieve the desired result, e.g., to treat the disease or condition. Anysubject can be treated in accordance with the present invention,including, e.g., mammals (e.g., humans; non-human primates; monkeys;livestock, such as cows, pigs, and sheep; dogs; cats; rodents; rats;mice), and birds (e.g., chicken; turkey; and ducks). See, also any ofthe subjects listed in Table 5.

Treatment of the virus infections and diseases caused or associated withsuch infections according to the invention include not only thetreatment of subjects who are infected by the virus, but also thetreatment of subjects in which the infection or disease has not yetappeared, become symptomatic, or erupted. The present invention furtherrelates to preventing or reducing recurring eruptions or attacksassociated with viral infection. The term “treating” is usedconventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving, etc.,one or more symptoms of the viral infection or associated disease.

Furthermore compounds and combinations according to the inventioninhibit replication of Flaviviridae viruses and show further positivetherapeutic effects. Also compounds and combinations according to thepresent invention can be used for treating Flaviviridae virusesinfections with virus lines which are resistant to standard therapies.

Examples of Flaviviridae viruses are the genus flavivirus and pestivirussuch as yellow fever virus, denguevirus (e.g. species 1-4), west nilefever virus, spring-summer encephalitis virus, Omsk-hemorrhagic fevervirus, bovine virus-diarrhea-virus and swine fever virus, and hepatitisC.

Examples of diseases caused by Flaviviridae viruses infections include,but are not limited to, e.g. encephalitis, encephalomyelitis, Denguefever (e.g., DEN-1, 2, 3, -4), Yellow fever (e.g., hemorrhagic fever),St. Louis encephalitis, Japanese encephalitis, Murray Valleyencephalitis, and West Nile, Rocio, Tick-borne encephalitis, Omskhemorrhagic fever, Kyasanur Forest disease (e.g., hemorrhagic fever),and Powassan (encephalitis; meningoencephalitis).

The compounds and combinations according to the present invention can beused for manufacture of a medicament for treating Picornaviridae virusesinfections and/or diseases caused by such infections. Also the presentinvention provides methods of treating Picornaviridae viruses infectionsand/or diseases caused by such infections comprising administeringeffective amounts of at least one compound of formula I and optionallyat least one further therapeutic agent according to the invention. An“effective amount” is the quantity of the compound that is useful toachieve the desired result, e.g., to treat the disease or condition. Anysubject can be treated in accordance with the present invention,including, e.g., mammals (e.g., humans; non-human primates; monkeys;livestock, such as cows, pigs, and sheep; dogs; cats; rodents; rats;mice), and birds (e.g., chicken; turkey; and ducks). See, also any ofthe subjects listed in Table 6.

Treatment of the virus infections and diseases caused or associated withsuch infections according to the invention include not only thetreatment of subjects who are infected by the virus, but also thetreatment of subjects in which the infection or disease has not yetappeared, become symptomatic, or erupted. The present invention furtherrelates to preventing or reducing recurring eruptions or attacksassociated with viral infection. The term “treating” is usedconventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving, etc.,one or more symptoms of the viral infection or associated disease.

Furthermore compounds and combinations according to the inventioninhibit replication of Picornaviridae viruses and show further positivetherapeutic effects. Also compounds and combinations according to thepresent invention can be used for treating Picornaviridae virusesinfections with virus lines which are resistant to standard therapies.

Examples of Picornaviridae viruses are the genus enterovirus,cardiovirus, rhinovirus, aphtovirus and hepatovirus such as polioviruses(e.g. species 1, 2, 3), coxsackievirus (e.g. species A1-A22, A24),coxsackieviruses (e.g. species B1-B6), human echoviruses (e.g. species1-7, 9, 11-27, 29-33), human enteroviruses (e.g. species 68-71), humanrhinoviruses (e.g. species 1-100, 1A, 1B), hanks virus, rhinoviruses(e.g. species 1, 2), and the foot and mouth disease viruses (e.g.species 0, A, C, SAT1-3, ASIA1).

Examples of diseases caused by Picornaviridae viruses infections inhuman include, but are not limited to, e.g. aseptic meningitis,poliomyelitis, herpangina, pleurodynia (Bornholm disease), myositis,rhabdomyolysis, diabetes type I, summer fever and myocarditis.

Examples of a picornaviridae virus and the disease associated with it,include, but are not limited to, Poliovirus (3 serotypes), e.g., polio;Coxsackie A virus (23 serotypes), e.g., herpangina (infection of oralmucosal cells); aseptic meningitis; common cold (upper respiratory tractinfection); epidemic myalgia (including, pleurodynia, Bornholm disease,devil's grip); hand, foot, mouth disease (infection of epithelial cellsof the skin and oral mucosa); Coxsackie B virus (6 serotypes), e.g.,aseptic meningitis; epidemic myalgia (including, pleurodynia, Bornholmdisease, devil's grip); myocarditis; pericarditis; Echovirus (32serotypes), e.g., aseptic meningitis; Boston exanthem (epithelial cellinfection); cerebellar ataxia; pneumonitis; Rhinovirus (113 serotypes),e.g., common cold; and Hepatitis A virus, e.g., infectious hepatitis.

Administration

Compounds or drug combinations of the present invention can beadministered in any form by any effective route, including, e.g., oral,parenteral, enteral, intravenous, intraperitoneal, topical, transdermal(e.g., using any standard patch), ophthalmic, nasally, local, non-oral,such as aerosal, inhalation, subcutaneous, intramuscular, buccal,sublingual, rectal, vaginal, intra-arterial, and intrathecal, etc. Theycan be administered alone, or in combination with any ingredient(s),active or inactive.

Preference is given to an oral administration.

Compounds or drug combinations of the present invention can be convertedin a known manner into the usual formulations, which may be liquid orsolid formulations e.g. without limitation normal and enteric coatedtablets, capsules, pills, powders, granules, elixirs, tinctures,solution, suspensions, syrups, solid and liquid aerosols and emulsions.

Examples of solid formulations for oral administration are described inU.S. provisional application Nos. 60/605,753 and 60/658,827.

The combinations of the present invention can be administered at anytime and in any effective form. For example, the compounds can beadministered simultaneously, e.g., as a single composition or dosageunit (e.g., a pill or liquid containing both compositions), or they canbe administered as separate compositions, but at the same time (e.g.,where one drug is administered intravenously and the other isadministered orally or intramuscularly). The drugs can also beadministered sequentially at different times. Agents can be formulatedconventionally to achieve the desired rates of release over extendedperiod of times, e.g., 12-hours, 24-hours. This can be achieved by usingagents and/or their derivatives which have suitable metabolichalf-lives, and/or by using controlled release formulations.

The drug combinations can be synergistic, e.g., where the joint actionof the drugs is such that the combined effect is greater than thealgebraic sum of their individual effects. Thus, reduced amounts of thedrugs can be administered, e.g., reducing toxicity or other deleteriousor unwanted effects, and/or using the same amounts as used when theagents are administered alone, but achieving greater efficacy. Thereduced amounts of the drugs can be lower then used in a standardtherapy wherein e.g. the single drug is administered.

Compounds or drug combinations of the present invention can be furthercombined with any other suitable additive or pharmaceutically acceptablecarrier. Such additives include any of the substances already mentioned,as well as any of those used conventionally, such as those described inRemington: The Science and Practice of Pharmacy (Gennaro and Gennaro,eds, 20th edition, Lippincott Williams & Wilkins, 2000); Theory andPractice of Industrial Pharmacy, (Lachman et al., eds., 3rd edition,Lippincott Williams & Wilkins, 1986); Encyclopedia of PharmaceuticalTechnology (Swarbrick and Boylan, eds., 2nd edition, Marcel Dekker,2002). These can be referred to herein as “pharmaceutically acceptablecarriers” to indicate they are combined with the active drug and can beadministered safely to a subject for therapeutic purposes.

In addition, compounds or drug combinations of the present invention canbe administered with other active agents or other therapies that areutilized to treat any of the above-mentioned diseases and/or conditions.

Other therapies according to the invention include, but are not limitedto, physical or mechanical therapy such as electrical stimulation,acupuncture, magnet therapy or topical use of polyurethane films.

The present invention provides also combinations of at least onecompound of Formula I and at least one other therapeutic agent mentionedabove useful in treating a disease or disorder. “Combinations” for thepurposes of the invention include:

-   -   single compositions or dosage forms which contain at least one        compound of Formula I and at least one other therapeutic agent        mentioned above;    -   combination packs containing at least one compound of Formula I        and at least one other therapeutic agent mentioned above to be        administered concurrently or sequentially;    -   kits which comprise at least one compound of Formula I and at        least one other therapeutic agent mentioned above packaged        separate from one another as unit dosages or as independent unit        dosages, with or without instructions that they be administered        concurrently or sequentially; and    -   separate independent dosage forms of at least one compound of        Formula I and at least one other therapeutic agent mentioned        above which cooperate to achieve a therapeutic effect, e.g.,        treatment of the same disease, when administered concurrently or        sequentially.

The dosage of each agent of the combination can be selected withreference to the other and/or the type of disease and/or the diseasestatus in order to provide the desired therapeutic activity. Forexample, the active agents in the combination can be present andadministered in a fixed combination: “Fixed combination” is intendedhere to mean pharmaceutical forms in which the components are present ina fixed ratio that provides the desired efficacy. These amounts can bedetermined routinely for a particular patient, where various parametersare utilized to select the appropriate dosage (e.g., type of disease,age of patient, disease status, patient health, weight, etc.), or theamounts can be relatively standard.

The amount of the administered active ingredient can vary widelyaccording to such considerations as the particular compound and dosageunit employed, the mode and time of administration, the period oftreatment, the age, sex, and general condition of the patient treated,the nature and extent of the condition treated, the rate of drugmetabolism and excretion, the potential drug combinations and drug-druginteractions, and the like.

Preference is given to an amount of the compound of formula I from 20 to2000 mg, preferably from 40 to 800 mg, more preferably from 50 to 600mg.

Particular preference is given to an amount of p-toluenesulfonic acidsalt of4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide in the pharmaceutical composition from 27 to 2740 mg,preferably from 54 to 1096, more preferably from 68 to 822 mg.

In another embodiment of the invention the compound of formula I isadministered in combination with at least one further therapeutic agentin an amount that those of ordinary skill in the art can determine bytheir professional judgement.

The pharmaceutical composition according to the invention isadministered one or more, preferably up to three, more preferably up totwo times per day. Preference is given to an administration via the oralroute. With each administration the number of tablets or capsules takenin at the same time should not exceed two.

Nevertheless, it may in some cases be advantageous to deviate from theamounts specified, depending on body weight, individual behaviour towardthe active ingredient, type of preparation and time or interval overwhich the administration is effected. For instance, less than theaforementioned minimum amounts may be sufficient in some cases, whilethe upper limit specified has to be exceeded in other cases. In the caseof administration of relatively large amounts, it may be advisable todivide these into several individual doses over the day.

The combination can comprise effective amounts of at least one compoundof Formula I and at least one other therapeutic agent mentioned above,which achieves a greater therapeutic efficacy than when either compoundis used alone. The combination can be useful to treat SARS-CoVinfections and/or SARS itself, where the therapeutic effect is notobserved when the agents are used alone, or where an enhanced effect isobserved when the combination is administered.

The relative ratios of each compound in the combination can also beselected based on their respective mechanisms of action and the diseasebiology. The relative ratios of each compound can vary widely and thisinvention includes combinations for treating SARS-CoV infections and/orSARS itself where the amounts of the formula I compound and the othertherapeutic agent can be adjusted routinely such that either is presentin higher amounts.

The release of one or more agents of the combination can also becontrolled, where appropriate, to provide the desired therapeuticactivity when in a single dosage form, combination pack, kit or when inseparate independent dosage forms.

Preference is given to a combination comprising at least one compound offormula I and lopinavir and/or ritonavir. More preferably a combinationcomprising4{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide (BAY 43-9006) or the p-toluenesulfonic acid salt of4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide and lopinavir and/or ritonavir is used.

The combination can comprise effective amounts of at least one compoundof Formula I and at least one other therapeutic agent mentioned above,which achieves a greater therapeutic efficacy than when either compoundis used alone. The combination can be useful to treat HIV infectionsand/or diseases caused by HIV infections, where the therapeutic effectis not observed when the agents are used alone, or where an enhancedeffect is observed when the combination is administered.

The relative ratios of each compound in the combination can also beselected based on their respective mechanisms of action and the diseasebiology. The relative ratios of each compound can vary widely and thisinvention includes combinations for treating HIV infections and/ordiseases caused by HIV infections where the amounts of the formula Icompound and the other therapeutic agent can be adjusted routinely suchthat either is present in higher amounts.

The release of one or more agents of the combination can also becontrolled, where appropriate, to provide the desired therapeuticactivity when in a single dosage form, combination pack, kit or when inseparate independent dosage forms.

Preference is given to a combination comprising at least one compound offormula I and indinavir, zidovudine, tenofovir, parapoxvirus ovis and/orlamivudin. More preferably a combination comprising4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide (BAY 43-9006) or the p-toluenesulfonic acid salt of4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide and indinavir, zidovudine, tenofovir, parapoxvirusovis and/or lamivudin is used.

The combination can comprise effective amounts of at least one compoundof Formula I and at least one other therapeutic agent mentioned above,which achieves a greater therapeutic efficacy than when either compoundis used alone. The combination can be useful to treat hepatitis virusinfections and/or diseases caused by hepatitis virus infections, wherethe therapeutic effect is not observed when the agents are used alone,or where an enhanced effect is observed when the combination isadministered.

The relative ratios of each compound in the combination can also beselected based on their respective mechanisms of action and the diseasebiology. The relative ratios of each compound can vary widely and thisinvention includes combinations for treating hepatitis virus infectionsand/or diseases caused by hepatitis virus infections where the amountsof the formula I compound and the other therapeutic agent can beadjusted routinely such that either is present in higher amounts.

The release of one or more agents of the combination can also becontrolled, where appropriate, to provide the desired therapeuticactivity when in a single dosage form, combination pack, kit or when inseparate independent dosage forms.

Preference is given to a combination comprising at least one compound offormula I and lamivudin and/or adevovir dipivoxil. More preferably acombination comprising4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide (BAY 43-9006) or the p-toluenesulfonic acid salt of4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide and lamivudin and/or adevovir dipivoxil is used.

The combination can comprise effective amounts of at least one compoundof Formula I and at least one other therapeutic agent mentioned above,which achieves a greater therapeutic efficacy than when either compoundis used alone. The combination can be useful to treat influenza virusinfections and/or diseases caused by influenza virus infections, wherethe therapeutic effect is not observed when the agents are used alone,or where an enhanced effect is observed when the combination isadministered.

The relative ratios of each compound in the combination can also beselected based on their respective mechanisms of action and the diseasebiology. The relative ratios of each compound can vary widely and thisinvention includes combinations for treating influenza virus infectionsand/or diseases caused by influenza virus infections where the amountsof the formula I compound and the other therapeutic agent can beadjusted routinely such that either is present in higher amounts.

The release of one or more agents of the combination can also becontrolled, where appropriate, to provide the desired therapeuticactivity when in a single dosage form, combination pack, kit or when inseparate independent dosage forms.

Preference is given to a combination comprising at least one compound offormula I and oseltamvir, zanamivir and/or pegylated interferon-α. Morepreferably a combination comprising4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide (BAY 43-9006) or the p-toluenesulfonic acid salt of4{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide and oseltamvir, zanamivir and/or pegylatedinterferon-α is used

The combination can comprise effective amounts of at least one compoundof Formula I and at least one other therapeutic agent mentioned above,which achieves a greater therapeutic efficacy than when either compoundis used alone. The combination can be useful to treat Herpesviridaeviruses infections and/or diseases. caused by Herpesviridae virusesinfections, where the therapeutic effect is not observed when the agentsare used alone, or where an enhanced effect is observed when thecombination is administered.

The relative ratios of each compound in the combination can also beselected based on their respective mechanisms of action and the diseasebiology. The relative ratios of each compound can vary widely and thisinvention includes combinations for treating Herpesviridae virusesinfections and/or diseases caused by Herpesviridae viruses infectionswhere the amounts of the formula I compound and the other therapeuticagent can be adjusted routinely such that either is present in higheramounts.

The release of one or more agents of the combination can also becontrolled, where appropriate, to provide the desired therapeuticactivity when in a single dosage form, combination pack, kit or when inseparate independent dosage forms.

Preference is given to a combination comprising at least one compound offormula I and acyclovir. More preferably a combination comprising4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide (BAY 43-9006) or the p-toluenesulfonic acid salt of4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide and acyclovir.

The combination can comprise effective amounts of at least one compoundof Formula I and at least one other therapeutic agent mentioned above,which achieves a greater therapeutic efficacy than when either compoundis used alone. The combination can be useful to treat Papovaviridaeviruses infections and/or diseases caused by Papovaviridae virusesinfections, where the therapeutic effect is not observed when the agentsare used alone, or where an enhanced effect is observed when thecombination is administered.

The relative ratios of each compound in the combination can also beselected based on their respective mechanisms of action and the diseasebiology. The relative ratios of each compound can vary widely and thisinvention includes combinations for treating Papovaviridae virusesinfections and/or diseases caused by Papovaviridae viruses infectionswhere the amounts of the formula I compound and the other therapeuticagent can be adjusted routinely such that either is present in higheramounts.

The release of one or more agents of the combination can also becontrolled, where appropriate, to provide the desired therapeuticactivity when in a single dosage form, combination pack, kit or when inseparate independent dosage forms.

Preference is given to a combination comprising at least one compound offormula I and interferon, imiquimod, resiquimod, podophyllin, bleomycinand/or retinoid. More preferably a combination comprising4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide (BAY 43-9006) or the p-toluenesulfonic acid salt of4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide and interferon, imiquimod, resiquimod, podophyllin,bleomycin and/or retinoid

The combination can comprise effective amounts of at least one compoundof Formula I and at least one other therapeutic agent mentioned above,which achieves a greater therapeutic efficacy than when either compoundis used alone. The combination can be useful to treat Poxyiridae virusesinfections and/or diseases caused by Poxyiridae viruses infections,where the therapeutic effect is not observed when the agents are usedalone, or where an enhanced effect is observed when the combination isadministered.

The relative ratios of each compound in the combination can also beselected based on their respective mechanisms of action and the diseasebiology. The relative ratios of each compound can vary widely and thisinvention includes combinations for treating Poxyiridae virusesinfections and/or diseases caused by Poxyiridae viruses infections wherethe amounts of the formula I compound and the other therapeutic agentcan be adjusted routinely such that either is present in higher amounts.

The release of one or more agents of the combination can also becontrolled, where appropriate, to provide the desired therapeuticactivity when in a single dosage form, combination pack, kit or when inseparate independent dosage forms.

Preference is given to a combination comprising at least one compound offormula I and cidofovir, interferon-β, interferon alfacon-1,interferon-α and/or pegylated interferon-α. More preferably acombination comprising4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide (BAY 43-9006) or the p-toluenesulfonic acid salt of4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide and cidofovir, interferon-β, interferon alfacon-1,interferon-α and/or pegylated interferon-α is used.

The combination can comprise effective amounts of at least one compoundof Formula I and at least one other therapeutic agent mentioned above,which achieves a greater therapeutic efficacy than when either compoundis used alone. The combination can be useful to treat Flaviviridaeviruses infections and/or diseases caused by Flaviviridae virusesinfections, where the therapeutic effect is not observed when the agentsare used alone, or where an enhanced effect is observed when thecombination is administered.

The relative ratios of each compound in the combination can also beselected based on their respective mechanisms of action and the diseasebiology. The relative ratios of each compound can vary widely and thisinvention includes combinations for treating Flaviviridae virusesinfections and/or diseases caused by Flaviviridae viruses infectionswhere the amounts of the formula I compound and the other therapeuticagent can be adjusted routinely such that either is present in higheramounts.

The release of one or more agents of the combination can also becontrolled, where appropriate, to provide the desired therapeuticactivity when in a single dosage form, combination pack, kit or when inseparate independent dosage forms.

Preference is given to a combination comprising at least one compound offormula I and ribavirin, interferon-11, interferon alfacon-1,interferon-α and/or pegylated interferon-α. More preferably acombination comprising4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide (BAY 43-9006) or the p-toluenesulfonic acid salt of4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide and ribavirin, interferon-β, interferon alfacon-1,interferon-α and/or pegylated interferon-α is used.

The combination can comprise effective amounts of at least one compoundof Formula I and at least one other therapeutic agent mentioned above,which achieves a greater therapeutic efficacy than when either compoundis used alone. The combination can be useful to treat virus infectionsaccording to the invention and/or diseases caused by such virusinfections, where the therapeutic effect is not observed when the agentsare used alone, or where an enhanced effect is observed when thecombination is administered.

The relative ratios of each compound in the combination can also beselected based on their respective mechanisms of action and the diseasebiology. The relative ratios of each compound can vary widely and thisinvention includes combinations for treating virus infections accordingto the invention and/or diseases caused by such virus infections wherethe amounts of the formula I compound and the other therapeutic agentcan be adjusted routinely such that either is present in higher amounts.

The release of one or more agents of the combination can also becontrolled, where appropriate, to provide the desired therapeuticactivity when in a single dosage form, combination pack, kit or when inseparate independent dosage forms.

Preference is given to a combination comprising at least one compound offormula I and interferon-β, interferon alfacon-1, interferon-α and/orpegylated interferon-α. More preferably a combination comprising4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide (BAY 43-9006) or the p-toluenesulfonic acid salt of4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide and interferon-β, interferon alfacon-1, interferon-αand/or pegylated interferon-α is used.

The combination can comprise effective amounts of at least one compoundof Formula I and at least one other therapeutic agent mentioned above,which achieves a greater therapeutic efficacy than when either compoundis used alone. The combination can be useful to treat Picornaviridaeviruses infections and/or diseases caused by Picornaviridae virusesinfections, where the therapeutic effect is not observed when the agentsare used alone, or where an enhanced effect is observed when thecombination is administered.

The relative ratios of each compound in the combination can also beselected based on their respective mechanisms of action and the diseasebiology. The relative ratios of each compound can vary widely and thisinvention includes combinations for treating Picornaviridae virusesinfections and/or diseases caused by Picornaviridae viruses infectionswhere the amounts of the formula I compound and the other therapeuticagent can be adjusted routinely such that either is present in higheramounts.

The release of one or more agents of the combination can also becontrolled, where appropriate, to provide the desired therapeuticactivity when in a single dosage form, combination pack, kit or when inseparate independent dosage forms.

Preference is given to a combination comprising at least one compound offormula I and ruprintrivir, pirodavir, parapoxvirus ovis and/orpegylated interferon-α. More preferably a combination comprising4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide (BAY 43-9006) or the p-toluenesulfonic acid salt of4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide and ruprintrivir, pirodavir, parapoxvirus ovis and/orpegylated interferon-α is used.

TABLE 1 (from the ICTVdB Index of Viruses on the worldwide web atncbi.nlm.nih.gov/ICTVdb/Ictv/fs_herpe.htm) Family 00.031. HerpesviridaeSubfamily 00.031.1. Alphaherpesvirinae Genus 00.031.1.01. SimplexvirusGenus 00.031.1.02. Varicellovirus Genus 00.031.1.03. Mardivirus (was“Marek's disease-like viruses”) Genus 00.031.1.04. Iltovirus (was“Infectious laryngotracheitis-like viruses”) Subfamily 00.031.2.Betaherpesvirinae Genus 00.031.2.01. Cytomegalovirus Genus 00.031.2.02.Muromegalovirus Genus 00.031.2.03. Roseolovirus Subfamily 00.031.3.Gammaherpesvirinae Genus 00.031.3.01. Lymphocryptovirus Genus00.031.3.02. Rhadinovirus Genus 00.031.0.01. Ictalurivirus (was“Ictalurid herpes-like viruses”) Subfamily 00.031.1. AlphaherpesvirinaeGenus 00.031.1.01. Simplexvirus Type Species 00.031.1.01.001. Humanherpesvirus 1 (HHV-1) List of Species in the Genus The ICTVdB virus codeand the viruses. Species names are in italics. Tentative virus speciesnames, alternative names (synonym), isolates, strains, serotypes,subspecies, or rejected names are not italicized. Virus codes, virusnames, arthropod vector and host names { }, serotypes, genome sequenceaccession numbers [ ] and assigned abbreviations ( ), are: Species,their serotypes, strains and isolates 00.031.1.01.006. Atelineherpesvirus 1 (AtHV-1) 00.031.1.01.006. (Spider monkey herpesvirus)00.031.1.01.002. Bovine herpesvirus 2 (BoHV-2) 00.031.1.01.002. (Bovinemamillitis virus) 00.031.1.01.005. Cercopithecine herpesvirus 1 (CeHV-1)00.031.1.01.005. (B-virus) 00.031.1.01.005. (Herpesvirus simiae)00.031.1.01.007. Cercopithecine herpesvirus 2 (CeHV-2) 00.031.1.01.007.(SA8) 00.031.1.01.009. Cercopithecine herpesvirus 16 (CeHV-16)00.031.1.01.009. (Herpesvirus papio 2) 00.031.1.01.003. Humanherpesvirus 1 [X14112] (HHV-1) 00.031.1.01.003. (Herpes simplex virus 1)00.031.1.01.004. Human herpesvirus 2 [Z86099] (HHV-2) 00.031.1.01.004.(Herpes simplex virus 2) 00.031.1.01.017. Macropodid herpesvirus 1(MaHV-1) 00.031.1.01.017. (Parma wallaby herpesvirus) 00.031.1.01.018.Macropodid herpesvirus 2 (MaHV-2) 00.031.1.01.018. (Dorcopsis wallabyherpesvirus) 00.031.1.01.008. Saimiriine herpesvirus 1 (SaHV-1)00.031.1.01.008. (Herpesvirus tamarinus) 00.031.1.01.008. (Marmosetherpesvirus) Genus 00.031.1.02 Varicellovirus Type Species00.031.1.02.001. Human herpesvirus 3 (HHV-3) List of Species in theGenus The ICTVdB virus code and the viruses. Species names are initalics. Tentative virus species names, alternative names (synonym),isolates, strains, serotypes, subspecies, or rejected names are notitalicized. Virus codes, virus names, arthropod vector and host names {}, serotypes, genome sequence accession numbers [ ] and assignedabbreviations ( ), are: Species, their serotypes, strains and isolates00.031.1.02.002. Bovine herpesvirus 1 [AJ004801] (BoHV-1)00.031.1.02.002. (Infectious bovine rhinotracheitis virus)00.031.1.02.003. Bovine herpesvirus 5 (BoHV-5) 00.031.1.02.003. (Bovineencephalitis virus) 00.031.1.02.004. Bubaline herpesvirus 1 (BuHV-1)00.031.1.02.004. (Water buffalo herpesvirus) 00.031.1.02.005. Canidherpesvirus 1 (CaHV-1) 00.031.1.02.005. (Canine herpesvirus)00.031.1.02.006. Caprine herpesvirus 1 (CpHV-1) 00.031.1.02.006. (Goatherpesvirus) 00.031.1.02.007. Cereopithecine herpesvirus 9 (CeHV-9)00.031.1.02.007. (Simian varicella virus) 00.031.1.02.007. (Liverpoolvervet herpesvirus) 00.031.1.02.007. (Patas monkey herpesvirus delta)00.031.1.02.007. (Medical Lake macaque herpesvirus) 00.031.1.02.008.Cervid herpesvirus 1 (CvHV-1) 00.031.1.02.008. (Red deer herpesvirus)00.031.1.02.009. Cervid herpesvirus 2 (CvHV-2) 00.031.1.02.009.(Reindeer herpesvirus) 00.031.1.02.010. Equid herpesvirus 1 [M86664](EHV-1) 00.031.1.02.010. (Equine abortion virus) 00.031.1.02.018. Equidherpesvirus 3 (EHV-3) 00.031.1.02.018. (Equine coital exanthema virus)00.031.1.02.011. Equid herpesvirus 4 [AF030027] (EHV-4) 00.031.1.02.011.(Equine rhinopneumonitis virus) 00.031.1.02.012. Equid herpesvirus 8(EHV-8) 00.031.1.02.012. (Asinine herpesvirus 3) 00.031.1.02.013. Equidherpesvirus 9 (EHV-9) 00.031.1.02.013. (Gazelle herpesvirus)00.031.1.02.014. Felid herpesvirus 1 (FeHV-1) 00.031.1.02.014. (Felineviral rhinotracheitis virus) 00.031.1.02.015. Human herpesvirus 3[X04370] (HHV-3) 00.031.1.02.015. (Varicella-zoster virus)00.031.1.02.016. Phocid herpesvirus 1 (PhoHV-1) 00.031.1.02.016. (Harborseal herpesvirus) 00.031.1.02.017. Suid herpesvirus 1 (SuHV-1)00.031.1.02.017. (Pseudorabies virus) (PRV) Tentative Species in theGenus 00.031.1.82.019. Equid herpesvirus 6 (EHV-6) 00.031.1.82.019.(Asinine herpesvirus 1) Genus 00.031.1.03. Mardivirus (was “Marek'sdisease-like viruses)” Type Species 00.031.1.03.001. Gallid herpesvirus2 (GaHV-2) List of Species in the Genus The ICTVdB virus code and theviruses. Species names are in italics. Tentative virus species names,alternative names (synonym), isolates, strains, serotypes, subspecies,or rejected names are not italicized. Virus codes, virus names,arthropod vector and host names { }, serotypes, genome sequenceaccession numbers [ ] and assigned abbreviations ( ), are: Species,their serotypes, strains and isolates 00.031.1.03.001. Gallidherpesvirus 2 (GaHV-2) 00.031.1.03.001. (Marek's disease herpesvirus 1)00.031.1.03.002. Gallid herpesvirus 3 (GaHV-3) 00.031.1.03.002. (Marek'sdisease herpesvirus 2) 00.031.1.03.003. Meleagrid herpesvirus 1 (MeHV-1)00.031.1.03.003. (Turkey herpesvirus 1) Tentative Species in the GenusNone reported. Genus 00.031.1.04. Iltovirus (was “Infectiouslaryngotracheitis-like viruses”) Type Species 00.031.1.04.001. Gallidherpesvirus 1 (GaHV-1) List of Species in the Genus The ICTVdB viruscode and the viruses. Species names are in italics. Tentative virusspecies names, alternative names (synonym), isolates, strains,serotypes, subspecies, or rejected names are not italicized. Viruscodes, virus names, arthropod vector and host names { }, serotypes,genome sequence accession numbers [ ] and assigned abbreviations ( ),are: Species, their serotypes, strains and isolates 00.031.1.04.001.Gallid herpesvirus 1 (GaHV-1) 00.031.1.04.001. (Infectiouslaryngotracheitis virus) Tentative Species in the Genus None reported.List of Unassigned Viruses in the Subfamily 00.031.1.00.041. Psittacidherpesvirus 1 (PsHV-1) 00.031.1.00.041. (Parrot herpesvirus)00.031.1.00.041. (Pacheco's disease virus) Subfamily 00.031.2.Betaherpesvirinae Genus 00.031.2.01 Cytomegalovirus Type Species00.031.2.01.001. Human herpesvirus 5 (HHV-5) List of Species in theGenus The ICTVdB virus code and the viruses. Species names are initalics. Tentative virus species names, alternative names (synonym),isolates, strains, serotypes, subspecies, or rejected names are notitalicized. Virus codes, virus names, arthropod vector and host names {}, serotypes, genome sequence accession numbers [ ] and assignedabbreviations ( ), are: Species, their serotypes, strains and isolates00.031.2.01.002. Cercopithecine herpesvirus 5 (CeHV-5) 00.031.2.01.002.(African green monkey cytomegalovirus) 00.031.2.01.003. Cercopithecineherpesvirus 8 (CeHV-8) 00.031.2.01.003. (Rhesus monkey cytomegalovirus)00.031.2.01.004. Human herpesvirus 5 [X17403] (HHV-5) 00.031.2.01.004.(Human cytomegalovirus) 00.031.2.01.005. Pongine herpesvirus 4 (PoHV-4)Tentative Species in the Genus 00.031.2.81.001. Aotine herpesvirus 1(AoHV-1) 00.031.2.81.001. (Herpesvirus aotus 1) 00.031.2.81.002. Aotineherpesvirus 3 (AoHV-3) 00.031.2.81.002. (Herpesvirus aotus 3) Genus00.031.2.02. Muromegalovirus Type Species 00.031.2.02.001. Muridcytomegalovirus 1 (MCMV-1) List of Species in the Genus The ICTVdB viruscode and the viruses. Species names are in italics. Tentative virusspecies names, alternative names (synonym), isolates, strains,serotypes, subspecies, or rejected names are not italicized. Viruscodes, virus names, arthropod vector and host names { }, serotypes,genome sequence accession numbers [ ] and assigned abbreviations ( ),are: Species, their serotypes, strains and isolates 00.031.2.02.001.Murid herpesvirus 1 [U68299] (MuHV-1) 00.031.2.02.001. (Mousecytomegalovirus 1) 00.031.2.02.002. Murid herpesvirus 2 (MuHV-2)00.031.2.02.002. (Rat cytomegalovirus) Tentative Species in the GenusNone reported Genus 00.031.2.03. Roseolovirus Type Species00.031.2.03.001. Human herpesvirus 6 (HHV-6) List of Species in theGenus The ICTVdB virus code and the viruses. Species names are initalics. Tentative virus species names, alternative names (synonym),isolates, strains, serotypes, subspecies, or rejected names are notitalicized. Virus codes, virus names, arthropod vector and host names {}, serotypes, genome sequence accession numbers [ ] and assignedabbreviations ( ), are: Species, their serotypes, strains and isolates00.031.2.03.001. Human herpesvirus 6 (HHV-6) 00.031.2.03.001.00.001.Human herpesvirus 6A (HHV-6A) 00.031.2.03.001.00.001.001. U1102 [X83413]00.031.2.03.001.00.002. Human herpesvirus 6B (HHV-6B) 00.031.2.03.002.Human herpesvirus 7 [U43400] (HHV-7) 00.031.2.03.002. Human herpesvirus7 [AF037218] Tentative Species in the Genus None reported. Subfamily00.031.3. Gammaherpesvirinae Genus 00.031.3.01. Lymphocryptovirus TypeSpecies 00.031.3.01.001. Human herpesvirus 4 (HHV-4) List of Species inthe Genus The ICTVdB virus code and the viruses. Species names are initalics. Tentative virus species names, alternative names (synonym),isolates, strains, serotypes, subspecies, or rejected names are notitalicized. Virus codes, virus names, arthropod vector and host names {}, serotypes, genome sequence accession numbers [ ] and assignedabbreviations ( ), are: Species, their serotypes, strains and isolates00.031.3.01.002. Cercopithecine herpesvirus 12 (CeHV-12)00.031.3.01.002. (Herpesvirus papio) 00.031.3.01.002. (Baboonherpesvirus) 00.031.3.01.003. Cercopithecine herpesvirus 14 (CeHV-14)00.031.3.01.003. (African green monkey EBV-like virus) 00.031.3.01.004.Cercopithecine herpesvirus 15 (CeHV-15) 00.031.3.01.004. (RhesusEBV-like virus) 00.031.3.01.005. Human herpesvirus 4 [V01555] (HHV-4)00.031.3.01.005. (Epstein-Barr virus) 00.031.3.01.006. Pongineherpesvirus 1 (PoHV-1) 00.031.3.01.006. (Herpesvirus pan)00.031.3.01.007. Pongine herpesvirus 2 (PoHV-2) 00.031.3.01.007.(Orangutan herpesvirus) 00.031.3.01.008. Pongine herpesvirus 3 (PoHV-3)00.031.3.01.008. (Gorilla herpesvirus) Tentative Species in the GenusNone reported. Genus 00.031.3.02. Rhadinovirus Type Species00.031.3.02.001. Saimiriine herpesvirus 2 (SaHV-2) List of Species inthe Genus The ICTVdB virus code and the viruses. Species names are initalics. Tentative virus species names, alternative names (synonym),isolates, strains, serotypes, subspecies, or rejected names are notitalicized. Virus codes, virus names, arthropod vector and host names {}, serotypes, genome sequence accession numbers [ ] and assignedabbreviations ( ), are: Species, their serotypes, strains and isolates00.031.3.02.003. Alcelaphine herpesvirus 1 (AIHV-1) 00.031.3.02.003.(Malignant catarrhal fever virus) 00.031.3.02.004. Alcelaphineherpesvirus 2 (AIHV-2) 00.031.3.02.004. (Hartebeest malignant catarrhalfever virus) 00.031.3.02.002. Ateline herpesvirus 2 (AtHV-2)00.031.3.02.002. (Herpesvirus ateles) (AtHV-2) 00.031.3.02.005. Bovineherpesvirus 4 (BoHV-4) 00.031.3.02.005. (Movar virus) 00.031.3.02.006.Cercopithecine herpesvirus 17 (CeHV-17) 00.031.3.02.006. (Rhesusrhadinovirus) (CeHV-17) 00.031.3.02.007. Equid herpesvirus 2 [U20824](EHV-2) 00.031.3.02.008. Equid herpesvirus 5 (EHV-5) 00.031.3.02.009.Equid herpesvirus 7 (EHV-7) 00.031.3.02.009. (Asinine herpesvirus 2)00.031.3.02.010. Hippotragine herpesvirus 1 (HiHV-1) 00.031.3.02.010.(Roan antelope herpesvirus) 00.031.3.02.011. Human herpesvirus 8[U75699] (HHV-8) 00.031.3.02.011. Human herpesvirus 8 [U75700] (HHV-8)00.031.3.02.011. Human herpesvirus 8 [U93872] (HHV-8) 00.031.3.02.011.(Kaposi's sarcoma-associated herpesvirus) 00.031.3.02.012. Muridherpesvirus 4 [U97553] (MuHV-4) 00.031.3.02.012. (Mouse herpesvirusstrain 68) 00.031.3.02.013. Ovine herpesvirus 2 (OvHV-2)00.031.3.02.013. (Sheep-associated malignant catarrhal fever of cattlevirus) 00.031.3.02.014. Saimiriine herpesvirus 2 [X64346] (SaHV-2)00.031.3.02.014. (Herpesvirus saimiri) Tentative Species in the Genus00.031.3.82.015. Leporid herpesvirus 1 (LeHV-1) 00.031.3.82.015.(Cottontail rabbit herpesvirus) 00.031.3.82.016. Leporid herpesvirus 2(LeHV-2) 00.031.3.82.016. (Herpesvirus cuniculi) 00.031.3.82.017.Leporid herpesvirus 3 (LeHV-1) 00.031.3.82.017. (Herpesvirus sylvilagus)00.031.3.82.018. Marmomid herpesvirus 1 (MaHV-1) 00.031.3.82.018.(Woodchuck herpesvirus marmota) 00.031.3.82.018. (Herpesvirus marmota)00.031.3.82.019. Retroperitoneal fibromatosis-associated herpesvirus(RFHV) List of Unassigned Species in the Subfamily 00.031.3.00.006.Callitrichine herpesvirus 1 (CalHV-1) 00.031.3.00.006. (Herpesvirussanguinus) 00.031.3.00.019. Callitrichine herpesvirus 3 (CalHV-3)00.031.3.00.020. Mustelid herpesvirus 1 (MusHV-1) Genus 00.031.0.01Ictalurivirus (was “Ictalurid Herpes-like viruses”) Type Species00.031.0.01.001. Ictalurid herpesvirus 1 (IcHV-1) List of Species in theGenus The ICTVdB virus code and the viruses. Species names are initalics. Tentative virus species names, alternative names (synonym),isolates, strains, serotypes, subspecies, or rejected names are notitalicized. Virus codes, virus names, arthropod vector and host names {}, serotypes, genome sequence accession numbers [ ] and assignedabbreviations ( ), are: Species, their serotypes, strains and isolates00.031.0.01.001. Ictalurid herpesvirus 1 [M75136] (IcHV-1)00.031.0.01.001. (Channel catfish herpesvirus) (CCHV) Tentative Speciesin the Genus None reported. List of Unassigned Viruses in the Family00.031.0.00.050. Acipenserid herpesvirus 1 (AciHV-1) 00.031.0.00.050.(White sturgeon herpesvirus 1) 00.031.0.00.051. Acipenserid herpesvirus2 (AciHV-2) 00.031.0.00.051. (White sturgeon herpesvirus 2)00.031.0.00.001. Acciptrid herpesvirus 1 (AcHV-1) 00.031.0.00.001. (Baldeagle herpesvirus) 00.031.0.00.002. Anatid herpesvirus 1 (AnHV-1)00.031.0.00.002. (Duck plague herpesvirus) 00.031.0.00.052. Anguillidherpesvirus 1 (AngHV-1) 00.031.0.00.052. (Japanese eel herpesvirus)00.031.0.00.004. Ateline herpesvirus 3 (AtHV-3) 00.031.0.00.004.(Herpesvirus ateles strain 73) 00.031.0.00.005. Boid herpesvirus 1(BaHV-1) 00.031.0.00.005. (Boa herpesvirus) 00.031.0.00.053.Callitrichine herpesvirus 2 (CaHV-2) 00.031.0.00.053. (Marmosetcytomegalovirus) 00.031.0.00.054. Caviid herpesvirus 1 (CvHV-1)00.031.0.00.054. (Guinea pig herpesvirus) 00.031.0.00.054. (Hsiungkaplow herpesvirus) 00.031.0.00.007. Caviid herpesvirus 3 (CvHV-3)00.031.0.00.007. (Guinea pig herpesvirus 3) 00.031.0.00.055. Cebineherpesvirus 1 (CbHV-1) 00.031.0.00.055. (Capuchin herpesvirus AL-5)00.031.0.00.056. Cebine herpesvirus 2 (CbHV-2) 00.031.0.00.056.(Capuchin herpesvirus AP-18) 00.031.0.00.057. Cercopithecine herpesvirus3 (CeHV-3) 00.031.0.00.057. (SA6 virus) 00.031.0.00.058. Cercopithecineherpesvirus 4 (CeHV-4) 00.031.0.00.058. (SA 15 virus) 00.031.0.00.008.Cercopithecine herpesvirus 10 (CeHV-10) 00.031.0.00.008. (Rhesusleukocyte associated herpesvirus strain 1) 00.031.0.00.009.Cercopithecine herpesvirus 13 (CeHV-13) 00.031.0.00.009. (Herpesviruscyclopsis) 00.031.0.00.011. Chelonid herpesvirus 1 (ChHV-1)00.031.0.00.011. (Gray patch disease of turtles) 00.031.0.00.012.Chelonid herpesvirus 2 (ChHV-2) 00.031.0.00.012. (Pacific pond turtleherpesvirus) 00.031.0.00.013. Chelonid herpesvirus 3 (ChHV-3)00.031.0.00.013. (Painted turtle herpesvirus) 00.031.0.00.014. Chelonidherpesvirus 4 (ChHV-4) 00.031.0.00.014. (Argentine turtle herpesvirus)00.031.0.00.015. Ciconiid herpesvirus 1 (CiHV-1) 00.031.0.00.015. (Blackstork herpesvirus) 00.031.0.00.016. Columbid herpesvirus 1 (CoHV-1)00.031.0.00.016. (Pigeon herpesvirus) 00.031.0.00.059. Cricetidherpesvirus (CrHV-1) 00.031.0.00.059. (Hamster herpesvirus)00.031.0.00.017. Cyprinid herpesvirus 1 (CyHV-1) 00.031.0.00.017. (Carppox herpesvirus) 00.031.0.00.060. Cyprinid herpesvirus 2 (CyHV-2)00.031.0.00.060. (Goldfish herpesvirus) 00.031.0.00.060. (Haematopoieticnecrosis herpesvirus of goldfish) 00.031.0.00.019. Elapid herpesvirus 1(EpHV-1) 00.031.0.00.019. (Indian cobra herpesvirus) 00.031.0.00.019.(Banded krait herpesvirus) 00.031.0.00.019. (Siamese cobra herpesvirus)00.031.0.00.018. Elephantid herpesvirus 1 (EiHV-1) 00.031.0.00.018.(Elephant loxondontal herpesvirus) 00.031.0.00.020. Erinaceidherpesvirus 1 (ErHV-1) 00.031.0.00.020. (European hedgehog herpesvirus)00.031.0.00.021. Esocid herpesvirus 1 (EsHV-1) 00.031.0.00.021.(Northern pike herpesvirus) 00.031.0.00.022. Falconid herpesvirus 1(FaHV-1) 00.031.0.00.022. (Falcon inclusion body disease)00.031.0.00.025. Gruid herpesvirus 1 (GrHV-1) 00.031.0.00.025. (Craneherpesvirus) 00.031.0.00.029. Lacertid herpesvirus 1 (LaHV-1)00.031.0.00.029. (Green lizard herpesvirus) 00.031.0.00.028. Lorisineherpesvirus 1 (LoHV-1) 00.031.0.00.028. (Kinkajou herpesvirus)00.031.0.00.028. (Herpesvirus pottos) 00.031.0.00.031. Murid herpesvirus3 (MuHV-3) 00.031.0.00.031. (Mouse thymic herpesvirus) 00.031.0.00.032.Murid herpesvirus 5 (MuHV-5) 00.031.0.00.032. (Field mouse herpesvirus)00.031.0.00.032. (Microtus pennsylvanicus herpesvirus) 00.031.0.00.033.Murid herpesvirus 6 (MuHV-6) 00.031.0.00.033. (Sand rat nuclearinclusion agents) 00.031.0.00.061. Ostreid herpesvirus 1 (OsHV-1)00.031.0.00.061. (Pacific oyster herpesvirus) 00.031.0.00.035. Ovineherpesvirus 1 (OvHV-1) 00.031.0.00.035. (Sheep pulmonary adenomatosisassociated herpesvirus) 00.031.0.00.036. Percid herpesvirus 1 (PeHV-1)00.031.0.00.036. (Walleye epidermal hyperplasia) 00.031.0.00.037.Perdicid herpesvirus 1 (PdHV-1) 00.031.0.00.037. (Bobwhite quailherpesvirus) 00.031.0.00.038. Phalacrocoracid herpesvirus 1 (PhHV-1)00.031.0.00.038. (Cormorant herpesvirus) 00.031.0.00.038. (Lake Victoriacormorant herpesvirus) 00.031.0.00.040. Pleuronectid herpesvirus(PiHV-1) 00.031.0.00.040. (Herpesvirus scophthalmus) 00.031.0.00.040.(Turbot herpesvirus) 00.031.0.00.042. Ranid herpesvirus 1 (RaHV-1)00.031.0.00.042. (Luck♯e♭ frog herpesvirus) 00.031.0.00.043. Ranidherpesvirus 2 (RaHV-2) 00.031.0.00.043. (Frog herpesvirus 4)00.031.0.00.044. Salmonid herpesvirus 1 (SaHV-1) 00.031.0.00.044.(Herpesvirus salmonis) 00.031.0.00.045. Salmonid herpesvirus 2 (SaHV-2)00.031.0.00.045. (Onchorhynchus masou herpesvirus) 00.031.0.00.063.Sciurid herpesvirus 1 (ScHV-1) 00.031.0.00.063. (European groundsquirrel cytomegalovirus) 00.031.0.00.046. Sciurid herpesvirus 2(ScHV-2) 00.031.0.00.046. (American ground squirrel herpesvirus)00.031.0.00.047. Sphenicid herpesvirus 1 (SpHV-1) 00.031.0.00.047.(Black footed penguin herpesvirus) 00.031.0.00.048. Strigid herpesvirus1 (StHV-1) 00.031.0.00.048. (Owl hepatosplenitis herpesvirus)00.031.0.00.062. Suid herpesvirus 2 (SuHV-2) 00.031.0.00.062. (Swinecytomegalovirus) 00.031.0.00.049. Tupaiid herpesvirus 1 (TuHV-1)00.031.0.00.049. (Tree shrew herpesvirus)

TABLE 2 (from worldwide web atncbi.nlm.nih.gov/ICTVdb/Ictv/fs_papov.htm) Family Papovaviridae 1. GenusPolyomavirus 2. Genus Papillomavirus Genus Polyomavirus Type Speciesmurine polyomavirus (strain A2) (PyV) Taxonomic Structure of the GenusSpecies in the Genus Virus name (synonym) followed by [Genomic sequenceaccession number] (Acronym) African green monkey polyomavirus (LPV)(B-lymphotropic papovavirus strain K38) [K02562] baboon polyomavirus 2(PPV-2) BK virus (strain Dun) [J02038] (BKV) bovine polyomavirus (BPyV)(stump-tailed macaque virus) (fetal rhesus kidney virus) [D00755]budgerigar fledgling disease virus (BFDV) hamster polyomavirus [X02449](HaPV) JC virus (strain Mad1) [J02226] (JCV) murine polyomavirus[M55904] (KV) (mice pneumotropic virus) (Kilham strain, or K virus)murine polyomavirus (strain A2) [J02288] (PyV) rabbit kidney vacuolatingvirus (RKV) simian agent virus 12 (SAV-12) simian virus 40 (strain 776)[J02400] (SV-40) Genus Papillomavirus Type Species cottontail rabbitpapillomavirus (Shope) (CRPV) Taxonomic Structure of the Genus Membersof this genus are known from humans (more than 63 types, HPV-1, etc.),chimpanzee, colobus and rhesus monkeys, cow (6 types), deer, dog, horse,sheep, elephant, elk, opossum, multimammate and European harvest mouse,turtle, chaffinch and parrot. Species in the Genus Virus name (synonym)followed by [Genomic sequence accession number] (Acronym) bovinepapillomavirus 1 [X02346] (BPV-1) bovine papillomavirus 2 [M20219](BPV-2) bovine papillomavirus 4 [X05817] (BPV-4) canine oralpapillomavirus (COPV) chaffinch papillomavirus (ChPV) cottontail rabbitpapillomavirus (Shope) [K02708] (CRPV) deer papillomavirus [M11910](DPV) (deer fibroma virus) elephant papillomavirus (EPV) equinepapillomavirus (EqPV) European elk papillomavirus [M15953] (EEPV) humanpapillomavirus 1a [V01116] (HPV-1a) human papillomavirus 5 (HPV-5) humanpapillomavirus 6b (HPV-6b) human papillomavirus 8 (HPV-8) humanpapillomavirus 11 [M14119] (HPV-11) human papillomavirus 16 [K02718](HPV-16) human papillomavirus 18 [X05015] (HPV-18) human papillomavirus31 [J04353] (HPV-31) human papillomavirus 33 [M12732] (HPV-33)multimammate mouse papillomavirus (MnPV) rabbit oral papillomavirus(ROPV) reindeer papillomavirus (RePV) rhesus monkey papillomavirus(RMPV) sheep papillomavirus (SPV)

TABLE 3 HPV type and disease association (from Burd et al., ClinicalMicrobiol. Rev., 16: 1-17, Jan. 2003) Order indicates relativefrequency; bold and underline indicate most frequent association DiseaseHPV type Plantar warts 1 , 2, 4, 63 Common warts 2, 1 , 7, 4, 26, 27,29, 41, 57, 65, 77, 1, 3, 4, 10, 28 Flat warts 3, 10 , 26, 27, 28, 38,41, 49, 75, 76 Other cutaneous lesions 6, 11, 16, 30, 33, 36, 37, 38,41, 48, (e.g., epidermoid cysts, 60, 72, 73 laryngeal carcinoma)Epidermodysplasia 2, 3, 10, 5, 8, 9, 12, 14, 15, 17 , 19, 20, 21,verruciformis 22, 23, 24, 25, 36, 37, 38, 47, 50 Recurrent respiratory6, 11 papillomatosis Focal epithelial hyperplasia 13, 32 of HeckConjunctival 6, 11, 16 papillomas/carcinomas Condyloma acuminata 6, 11 ,30, 42, 43, 45, 51, 54, 55, 70 (genital warts) Cervical intraepithelialneoplasia Unspecified 30, 34, 39, 40, 53, 57, 59, 61, 62, 64, 66, 67,68, 69 Low risk 6, 11 , 16, 18, 31, 33, 35, 42, 43, 44, 45, 51, 52, 74High risk 16, 18 , 6, 11, 31, 34, 33, 35, 39, 42, 44, 45, 51, 52, 56,58, 66 Cervical carcinoma 16, 18 , 31, 45, 33, 35, 39, 51, 52, 56, 58,66, 68, 70

TABLE 4 (from the ICTVdB Index of Viruses on the worldwide web atncbi.nlm.nih.gov/ICTVdb/Ictv/fs_poxvi.htm) Taxonomic Structure of theFamily Family 00.058. Poxviridae Subfamily 00.058.1. ChordopoxvirinaeGenus 00.058.1.01. Orthopoxvirus Genus 00.058.1.02. Parapoxvirus Genus00.058.1.03. Avipoxvirus Genus 00.058.1.04. Capripoxvirus Genus00.058.1.05. Leporipoxvirus Genus 00.058.1.06. Suipoxvirus Genus00.058.1.07. Molluscipoxvirus Genus 00.058.1.08. Yatapoxvirus00.058.1.00. Unassigned viruses in the Subfamily Subfamily 00.058.2.Entomopoxvirinae Genus 00.058.2.01. Alphaentomopoxvirus Genus00.058.2.02. Betaentomopoxvirus Genus 00.058.2.03. Gammaentomopoxvirus00.058.2.00. Unassigned viruses in the Family Subfamily 00.058.1.Chordopoxvirinae Genus 00.058.1.01. Orthopoxvirus Type Species00.058.1.01.001. Vaccinia virus (VACV) List of Species in the Genus TheICTVdB virus code and the virus names. Species names are in italics. Allother virus names are not italicized and their taxonomic status iscolor-coded as follows: alternative names (synonym), isolates, strains,serotypes, subspecies, reclassified or rejected names. Virus codes,virus names, genome sequence accession numbers [ ], and assignedabbreviations ( ), are: Species, their serotypes, strains and isolates00.058.1.01.003. Camelpox virus [S51129] (CMLV) 00.058.1.01.003. {camel}00.058.1.01.004. Cowpox virus [M19531] (CPXV) 00.058.1.01.004. {rodents,felines, bovines, human} 00.058.1.01.005. Ectromelia virus [M83102](ECTV) 00.058.1.01.005. (Mousepox) 00.058.1.01.005. {reservoir unknown}00.058.1.01.006. Monkeypox virus [K02025] (MPXV) 00.058.1.01.006.{rodents, primates, human} 00.058.1.01.008. Raccoonpox virus [M94169](RCNV) 00.058.1.01.008. {North America raccoon} 00.058.1.01.009.Taterapox virus (GBLV) 00.058.1.01.009. {African gerbil}00.058.1.01.010. Vaccinia virus [M35027] (VACV) 00.058.1.01.010. {nonatural reservoir} 00.058.1.01.010.01. Buffalopox virus [U87233] (BPXV)00.058.1.01.010.01. {buffalo, cattle, human} 00.058.1.01.010.02.Rabbitpox virus [M60387] (RPXV) 00.058.1.01.010.02. {colonized rabbit,no natural reservoir} 00.058.1.01.011. Variola virus [K02031] (VARV)00.058.1.01.011. {human; eradicated from nature} 00.058.1.01.012.Volepox virus (VPXV) 00.058.1.01.012. {California pinon mouse and voles}Tentative Species in the Genus 00.058.1.81.013. Skunkpox virus (SKPV)00.058.1.81.013. {North American striped skunk} 00.058.1.81.014. UasinGishu disease virus (UGDV) 00.058.1.81.014. {Central African horses}Genus 00.058.1.02. Parapoxvirus Type Species 00.058.1.02.001. Orf virus(ORF) List of Species in the Genus The ICTVdB virus code and the virusnames. Species names are in italics. All other virus names are notitalicized and their taxonomic status is color-coded as follows:alternative names (synonym), isolates, strains, serotypes, subspecies,reclassified or rejected names. Virus codes, virus names, genomesequence accession numbers [ ], and assigned abbreviations ( ), are:Species, their serotypes, strains and isolates 00.058.1.02.002. Bovinepapular stomatitis virus (BPSV) 00.058.1.02.002. {bovines, human}00.058.1.02.003. Orf virus [M30023] (ORFV) 00.058.1.02.003. (Contagiouspustular dermatitis virus) 00.058.1.02.003. (Contagious ecthyma virus)00.058.1.02.003. {Sheep, goats, musk oxen, human, deer} 00.058.1.02.004.Parapoxvirus of red deer in New Zealand (PVNZ) 00.058.1.02.005.Pseudocowpox virus (PCPV) 00.058.1.02.005. (Milker's nodule virus)00.058.1.02.005. (ParaVaccinia virus) 00.058.1.02.005. {Bovines, human}00.058.1.02.006. Squirrel parapoxvirus (SPPV) Tentative Species in theGenus 00.058.1.82.007. Auzduk disease virus 00.058.1.82.007. (Camelcontagious ecthyma virus) 00.058.1.82.008. Chamois contagious ecthymavirus 00.058.1.82.009. Sealpox virus Genus 00.058.1.03. Avipoxvirus TypeSpecies 00.058.1.03.001. Fowlpox virus (FWPV) List of Species in theGenus The ICTVdB virus code and the virus names. Species names are initalics. All other virus names are not italicized and their taxonomicstatus is color-coded as follows: alternative names (synonym), isolates,strains, serotypes, subspecies, reclassified or rejected names. Viruscodes, virus names, genome sequence accession numbers [ ], and assignedabbreviations ( ), are: Species, their serotypes, strains and isolates00.058.1.03.002. Canarypox virus (CNPV) 00.058.1.03.003. Fowlpox virus[X17202] (FWPV) 00.058.1.03.003. Fowlpox virus [D00295] (FWPV)00.058.1.03.003. Fowlpox virus [AF198100] (FWPV) 00.058.1.03.004.Juncopox virus (JNPV) 00.058.1.03.005. Mynahpox virus (MYPV)00.058.1.03.006. Pigeonpox virus [M88588] (PGPV) 00.058.1.03.007.Psittacinepox virus (PSPV) 00.058.1.03.008. Quailpox virus (QUPV)00.058.1.03.009. Sparrowpox virus (SRPV) 00.058.1.03.010. Starlingpoxvirus (SLPV) 00.058.1.03.011. Turkeypox virus (TKPV Tentative Species inthe Genus 00.058.1.83.012. Crowpox virus (CRPV 00.058.1.83.013.Peacockpox virus (PKPV 00.058.1.83.014. Penguinpox virus (PEPV) Genus00.058.1.04. Capripoxvirus Type Species 00.058.1.04.001. Sheeppox virus(SPPV) List of Species in the Genus The ICTVdB virus code and the virusnames. Species names are in italics. All other virus names are notitalicized and their taxonomic status is color-coded as follows:alternative names (synonym), isolates, strains, serotypes, subspecies,reclassified or rejected names. Virus codes, virus names, genomesequence accession numbers [ ], and assigned abbreviations ( ), are:Species, their serotypes, strains and isolates 00.058.1.04.002. Goatpoxvirus (GTPV) 00.058.1.04.003. Lumpy skin disease virus (LSDV)00.058.1.04.004. Sheeppox virus [M28823] (SPPV) 00.058.1.04.004.Sheeppox virus [M30039] (SPPV) 00.058.1.04.004. Sheeppox virus [D00423](SPPV) 00.058.1.04.004. Sheeppox virus [S78201] (SPPV) Tentative Speciesin the Genus None reported. Genus 00.058.1.05. Leporipoxvirus TypeSpecies 00.058.1.05.001. Myxoma virus (MYXV) List of Species in theGenus The ICTVdB virus code and the virus names. Species names are initalics. All other virus names are not italicized and their taxonomicstatus is color-coded as follows: alternative names (synonym), isolates,strains, serotypes, subspecies, reclassified or rejected names. Viruscodes, virus names, genome sequence accession numbers [ ], and assignedabbreviations ( ), are: Species, their serotypes, strains and isolates00.058.1.05.002. Hare fibroma virus (FIBV) 00.058.1.05.002. {Europeanhare} 00.058.1.05.003. Myxoma virus [M93049] (MYXV) 00.058.1.05.004.Rabbit fibroma virus [M14899] (SFV) 00.058.1.05.004. (Shope fibromavirus) 00.058.1.05.005. Squirrel fibroma virus (SQFV) Tentative Speciesin the Genus None reported. Genus 00.058.1.06. Suipoxvirus Type Species00.058.1.06.001. Swinepox virus (SWPV) List of Species in the Genus TheICTVdB virus code and the virus names. Species names are in italics. Allother virus names are not italicized and their taxonomic status iscolor-coded as follows: alternative names (synonym), isolates, strains,serotypes, subspecies, reclassified or rejected names. Virus codes,virus names, genome sequence accession numbers [ ], and assignedabbreviations ( ), are: Species, their serotypes, strains and isolates00.058.1.06.001. Swinepox virus [M59931] (SWPV) 00.058.1.06.001.Swinepox virus [M64000] (SWPV) Tentative Species in the Genus Nonereported. Genus 00.058.1.07. Molluscipoxvirus Type Species00.058.1.07.001. Molluscum contagiosum virus (MOCV) List of Species inthe Genus The ICTVdB virus code and the virus names. Species names arein italics. All other virus names are not italicized and their taxonomicstatus is color-coded as follows: alternative names (synonym), isolates,strains, serotypes, subspecies, reclassified or rejected names. Viruscodes, virus names, genome sequence accession numbers [ ], and assignedabbreviations ( ), are: Species, their serotypes, strains and isolates00.058.1.07.001. Molluscum contagiosum virus [M63487] (MOCV)00.058.1.07.001. Molluscum contagiosum virus [U60315] (MOCV) TentativeSpecies in the Genus Unnamed viruses of horses, donkeys, chimpanzeesGenus 00.058.1.08. Yatapoxvirus Type Species 00.058.1.08.001. Yabamonkey tumor virus (YMTV) List of Species in the Genus The ICTVdB viruscode and the virus names. Species names are in italics. All other virusnames are not italicized and their taxonomic status is color-coded asfollows: alternative names (synonym), isolates, strains, serotypes,subspecies, reclassified or rejected names. Virus codes, virus names,genome sequence accession numbers [ ], and assigned abbreviations ( ),are: Species, their serotypes, strains and isolates 00.058.1.08.002.Tanapox virus (TANV) 00.058.1.08.003. Yaba monkey tumor virus [D26580](YMTV) Tentative Species in the Genus None reported. List of UnassignedViruses in the Subfamily 00.058.1.00.001. California harbor sealpoxvirus {May also infect dog, cat} (SPV) The viruses, their host { }and assigned 00.058.1.00.002. Cotia virus [D45170] {sentinel mice,Brazil} (CPV) abbreviations ( ) are: 00.058.1.00.003. Dolphin poxvirus{Bottle-nose dolphin} (DOV) 00.058.1.00.004. Embu virus {Mosquitoes,Human blood} (ERV) 00.058.1.00.005. Grey kangaroo poxvirus (KXV)00.058.1.00.006. Marmoset poxvirus (MPV) 00.058.1.00.007. Molluscum-likepoxvirus {Horse, donkey, chimpanzee} (MOV) 00.058.1.00.014. Mule deerpoxvirus {Odocoileus hemionus, Wyoming} (DPV) 00.058.1.00.008. Nilecrocodile poxvirus (CRV) 00.058.1.00.009. Quokka poxvirus {marsupial,Australia} (QPV) 00.058.1.00.010. Red kangaroo poxvirus (KPV)00.058.1.00.011. Salanga poxvirus {Aethomys medicatus, Cent. Afr. Rep}(SGV) 00.058.1.00.012. Spectacled caiman poxvirus (RPV) 00.058.1.00.013.Vole poxvirus {vole, Turkmenia} (VPV) 00.058.1.00.015. Yoka poxvirus{Aedes simpsoni, Centr. Afr. Rep.} (YKV) Subfamily 00.058.2.Entomopoxvirinae Genus 00.058.2.01. Alphaentomopoxvirus Type Species00.058.2.01.001. Melolontha melolontha entomopoxvirus (MMEV) List ofSpecies in the Genus The ICTVdB virus code and the virus names. Speciesnames are in italics. All other virus names are not italicized and theirtaxonomic status is color-coded as follows: alternative names (synonym),isolates, strains, serotypes, subspecies, reclassified or rejectednames. Virus codes, virus names, genome sequence accession numbers [ ],and assigned abbreviations ( ), are: Species, their serotypes, strainsand isolates 00.058.2.01.002. Anomala cuprea entomopoxvirus (ACEV)00.058.2.01.003. Aphodius tasmaniae entomopoxvirus (ATEV)00.058.2.01.004. Demodema boranensis entomopoxvirus (DBEV)00.058.2.01.005. Dermolepida albohirtum entomopoxvirus (DAEV)00.058.2.01.006. Figulus subleavis entomopoxvirus (FSEV)00.058.2.01.007. Geotrupes sylvaticus entomopoxvirus (GSEV)00.058.2.01.008. Melolontha melolontha entomopoxvirus [X77616] (MMEV)00.058.2.01.009 Othnonius batesi entomopoxvirus {O. batesi (coleoptera)}(ObEPV) 00.058.2.01.010 Phyllopertha horticola entomopoxvirus (PhEPV){P. horticola (Coleoptera)} Tentative Species in the Genus00.058.2.81.011. Ips typographus entomopoxvirus (ItEPV) ICTV reportsnone. {I. typographus (coleoptera)} Genus 00.058.2.02.Betaentomopoxvirus Type Species 00.058.2.02.001. Amsacta mooreientomopoxvirus (AMEV) List of Species in the Genus The ICTVdB virus codeand the virus names. Species names are in italics. All other virus namesare not italicized and their taxonomic status is color-coded as follows:alternative names (synonym), isolates, strains, serotypes, subspecies,reclassified or rejected names. Virus codes, virus names, genomesequence accession numbers [ ], their ‘origins L = lepidopteran, O =orthopteran’ and assigned abbreviations ( ), are: 00.058.2.02.002.Acrobasis zelleri entomopoxvirus ‘L’ (AZEV) 00.058.2.02.001. Amsactamoorei entomopoxvirus ‘L’[M80924] (AMEV) 00.058.2.02.001. Amsacta mooreientomopoxvirus ‘L’[M77182] (AMEV) 00.058.2.02.003. Arphia conspersaentomopoxvirus ‘O’ (ACOEV) 00.058.2.02.004. Choristoneura biennisentomopoxvirus ‘L’[M34140] (CBEV) 00.058.2.02.004. Choristoneura biennisentomopoxvirus ‘L’[D10680] (CBEV) 00.058.2.02.005. Choristoneuraconflicta entomopoxvirus ‘L’ (CCEV) 00.058.2.02.006. Choristoneuradiversuma entomopoxvirus ‘L’ (CDEV) 00.058.2.02.013. Choristoneurafumiferana entomopoxvirus ‘L’[D10681] (CFEV) 00.058.2.02.013.Choristoneura fumiferana entomopoxvirus ‘L’[U10476] (CFEV)00.058.2.02.007. Chorizagrotis auxiliars entomopoxvirus ‘L’ (CXEV)00.058.2.02.014. Heliothis armigera entomopoxvirus ‘L’[AF019224] (HAEV)00.058.2.02.014. Heliothis armigera entomopoxvirus ‘L’[L08077] (HAEV)00.058.2.02.008. Locusta migratoria entomopoxvirus ‘O’ (LMEV)00.058.2.02.010. Oedaleus senigalensis entomopoxvirus ‘O’ (OSEV)00.058.2.02.011. Operophtera brumata entomopoxvirus ‘L’ (OBEV)00.058.2.02.012. Schistocera gregaria entomopoxvirus ‘O’ (SGEV)Tentative Species in the Genus 00.058.2.82.013. Pseudaletia separataentomopoxvirus ‘L’ (PsEPV) {P. separata (Lepidoptera)} Genus00.058.2.03. Gammaentomopoxvirus Type Species 00.058.2.03.001.Chironomus luridus entomopoxvirus CLEV) List of Species in the Genus TheICTVdB virus code and the virus names. Species names are in italics. Allother virus names are not italicized and their taxonomic status iscolor-coded as follows: alternative names (synonym), isolates, strains,serotypes, subspecies, reclassified or rejected names. Virus codes,virus names, genome sequence accession numbers [ ], and assignedabbreviations ( ), are: Species, their serotypes, strains and isolates00.058.2.03.002. Aedes aegypti entomopoxvirus (AAEV) 00.058.2.03.003.Camptochironomus tentans entomopoxvirus (CTEV) 00.058.2.03.004.Chironomus attenuatus entomopoxvirus (CAEV) 00.058.2.03.005. Chironomusluridus entomopoxvirus (CLEV) 00.058.2.03.006. Chironomus plumosusentomopoxvirus (CPEV) 00.058.2.03.007. Goeldichironomus haloprasimusentomopoxvirus (GHEV) Tentative Species in the Genus None reported. Listof Unassigned Viruses in the Subfamily The viruses, their host { } andassigned abbreviations ( ) are: 00.058.2.00.001. Diachasmimorphaentomopoxvirus (DIEVV) 00.058.2.00.009. Melanoplus sanguinipesentomopoxvirus ‘O’[AF063866] (MSEV)

TABLE 5 (from the ICTVdB Index of Viruses on the worldwide web atncbi.nlm.nih.gov/ICTVdb/Ictv/fs_herpe.htm) Taxonomic Structure of theFamily Family 00.026. Flaviviridae Genus 00.026.0.01. Flavivirus Genus00.026.0.02. Pestivirus Genus 00.026.0.03. Hepacivirus Genus00.026.0.01. Flavivirus Type Species 00.026.0.01.001. Yellow fever virus(YFV) List of Species in the Genus The ICTVdB virus code and theviruses. Official virus species names are in italics. Tentative virusspecies names, alternative names ( ), isolates, strains, serotypes,subspecies, or rejected names are not italicized. Virus codes, virusnames, arthropod vector and host names { }, serotypes, genome sequenceaccession numbers [ ] and assigned abbreviations ( ), are: Species,their serotypes, strains and isolates 1. Tick-borne viruses Mammaliantick-borne virus group 00.026.0.01.016. Gadgets Gully virus [AF013374](GGYV) 00.026.0.01.022. Kadam virus [AF013380] (KADV) 00.026.0.01.026.Kyasanur Forest disease virus [X74111] (KFDV) 00.026.0.01.027. Langatvirus (LGTV) 00.026.0.01.027.02.102.002. strain TP21 [M73835]00.026.0.01.027.02.102.002. strain TP21 [M86650] 00.026.0.01.034. Omskhemorrhagic fever virus [X66694] (OHFV) 00.026.0.01.036. Powassan virus[L06436] (POWV) 00.026.0.01.038. Royal Farm virus [AF013398] (RFV)00.026.0.01.038.02.102.003. Karshi virus [AF013381] (KSIV)00.026.0.01.046. Tick-borne encephalitis virus (TBEV)00.026.0.01.046.02.101. European subtype 00.026.0.01.046.02.101.004.Neudoerfl virus [M27157] (NEUV) 00.026.0.01.046.02.101.004. Neudoerflvirus [M33668] (NEUV) 00.026.0.01.046.02.102. Far Eastern subtype[X07755] 00.026.0.01.046.02.102.003. Sofjin virus [X07755] (SOFV)00.026.0.01.046.02.103. Sibirian subtype 00.026.0.01.046.02.103.001.Vasilchenko [L40361] 00.026.0.01.028. Louping ill virus (LIV)00.026.0.01.028.02.100.002. LIV strain 369/T2 [M59376]00.026.0.01.028.02.100.003. LIV strain SB 526 [M94957]00.026.0.01.028.02.100.003. LIV strain SB 526 [X59815]00.026.0.01.028.02.100.007. Negishi virus [M94956] (NEGV)00.026.0.01.028.02.101. Irish subtype [X86784] 00.026.0.01.028.02.102.British subtype [D12937] 00.026.0.01.028.02.103. Spanish subtype[X77470] 00.026.0.01.028.02.104. Turkish subtype [X69125] Seabirdtick-borne virus group 00.026.0.01.029. Meaban virus (MEAV)00.026.0.01.029.05.105.001. Brest ART707 [AF013386] 00.026.0.01.042.Saumarez Reef virus (SREV) 00.026.0.01.042.05.105.001. CSIRO-4 [X80589]00.026.0.01.047. Tyuleniy virus (TYUV) 00.026.0.01.047.05.105.001. ThreeArch Rock [X80588] 2. Mosquito-borne viruses Aroa virus group00.026.0.01.003. Aroa virus (AROAV) 00.026.0.01.003.03.001.001.VenA-1809 [AF013362] 00.026.0.01.003.03.002. Bussuquara virus (BSQV)00.026.0.01.003.03.002.001. BeAn 4073 [AF013366] 00.026.0.01.003.03.003.Iguape virus (IGUV) 00.026.0.01.003.03.003.001. SP An71686 [AF013375]00.026.0.01.003.03.004. Naranjal virus (NJLV)00.026.0.01.003.03.004.001. 25008 [AF013390] Dengue virus group00.026.0.01.013. Dengue virus (DENV) 00.026.0.01.013.08.201. Denguevirus 1 [M23027] (DENV-1) 00.026.0.01.013.08.202. Dengue virus 2[M19197] (DENV-2) 00.026.0.01.013.08.203. Dengue virus 3 [A34774](DENV-3) 00.026.0.01.013.08.204. Dengue virus 4 [M14931] (DENV-4)00.026.0.01.023. Kedougou virus (KEDV) 00.026.0.01.023.08.202.001. DakAar D1470 [AF013382] Japanese encephalitis virus group 00.026.0.01.009.Cacipacore virus (CPCV) 00.026.0.01.009.03.000.001. BeAn 327600[AF013367] 00.026.0.01.025. Koutango virus (KOUV)00.026.0.01.025.04.204.001. Dak Ar D1470 [AF013384] 00.026.0.01.019.Japanese encephalitis virus (JEV) 00.026.0.01.019.04.204.001. strainJaOArS982 [M18370] 00.026.0.01.032. Murray Valley encephalitis virus[X03467] (MVEV) 00.026.0.01.032.04.204.002. Alfuy virus [AF013360](ALFV) 00.026.0.01.044. St. Louis encephalitis virus [M16614] (SLEV)00.026.0.01.049. Usutu virus (USUV) 00.026.0.01.049.04.204.001.SAAR-1776 [AF013412] 00.026.0.01.051. West Nile virus (WNV)00.026.0.01.051.04.204.001. 33/G8; 34/F6 [M12294]00.026.0.01.051.04.204.005. Kunjin virus [D00246] (KUNV)00.026.0.01.052. Yaounde virus (YAOV) 00.026.0.01.052.03.204.001. DakArY276 [AF013413] (YAOV) Kokobera virus group 00.026.0.01.024. Kokoberavirus (KOKV) 00.026.0.01.024.04.204.001. AusMRM 281 [AF013383] (KOKV)00.026.0.01.024.04.204.008. Stratford virus [AF013407] (STRV) Ntayavirus group 00.026.0.01.004. Bagaza virus (BAGV)00.026.0.01.004.06.206.001. DakAr B209 [AF013363] (BAGV)00.026.0.01.017. Ilheus virus [AF013376] (ILHV)00.026.0.81.003.02.200.001. Rocio virus [AF013397] (ROCV)00.026.0.01.018. Israel turkey meningoencephalomyelitis virus (ITV)[AF013377] 00.026.0.01.033. Ntaya virus [AF013392] (NTAV)00.026.0.01.045. Tembusu virus [AF013408] (TMUV) Spondweni virus group00.026.0.01.055. Zika virus (ZIKV) 00.026.0.01.055.03.200.001. MR-766[AF013415] (ZIKAV) 00.026.0.01.055.03.200.002. Spondweni virus[AF013406] (SPOV) Yellow fever virus group 00.026.0.01.005. Banzi virus(BANV) 00.026.0.01.005.07.207.001. SAH 336 [L40951] 00.026.0.01.007.Bouboui virus (BOUV) 00.026.0.01.007.07.207.001. DakAr B490 [AF013364]00.026.0.01.014. Edge Hill virus (EHV) 00.026.0.01.014.07.207.001. AusC-281 [AF013372] 00.026.0.01.020. Jugra virus (JUGV)00.026.0.01.020.02.002.001. P9-314 [AF013378]00.026.0.01.039.03.003.001. Dak An D4600 [AF013400] 00.026.0.01.039.Saboya virus (SABV) 00.026.0.01.039.03.004. Potiskum virus (POTV)00.026.0.01.039.03.004.002. IBAN 10069 [AF013395] 00.026.0.01.043. Sepikvirus (SEPV) 00.026.0.01.043.02.002.001. MK7148 [AF013404]00.026.0.01.048. Uganda S virus (UGSV) 00.026.0.01.050. Wesselsbronvirus (WESSV) 00.026.0.01.053. Yellow fever virus (YFV)00.026.0.01.053.01.201.002. 17D (vaccine strain) [X03700]00.026.0.01.053.01.201.004. Pasteur 17D-204 (vaccine strain) [X15062]00.026.0.01.053.01.201.003. strain 1899/81 3. Viruses with no knownarthopod vector Entebbe virus group 00.026.0.01.015. Entebbe bat virus(ENTV) 00.026.0.01.015.03.003.001. UgIL-30 [AF013373]00.026.0.81.015.03.004. Sokoluk virus (SOKV) 00.026.0.81.015.03.004.001.LEIV-400K [AF013405] 00.026.0.01.054. Yokose virus (YOKV)00.026.0.01.054.06.206.001. Oita 36 [AB114858] Modoc virus group00.026.0.01.002. Apoi virus [AF013361] (APOIV) 00.026.0.01.011. CowboneRidge virus (CRV) 00.026.0.01.011.09.009.001. W-10986 [AF013370]00.026.0.01.021. Jutiapa virus (JUTV) 00.026.0.01.021.09.009.001. JG-128[AF013379] 00.026.0.01.030. Modoc virus (MODV)00.026.0.01.030.09.009.001. M544 [AF013387] 00.026.0.01.040. Sal Viejavirus (SVV) 00.026.0.01.040.09.009.001. 38TWM-106 [AF013401]00.026.0.01.041. San Perlita virus (SPV) 00.026.0.01.041.09.009.001.71V-1251 [AF013402] Rio Bravo virus group 00.026.0.01.008. Bukalasa batvirus (BBV) 00.026.0.01.008.03.003.001. UGBP-111 [AF013365]00.026.0.01.010. Carey Island virus (CIV) 00.026.0.01.010.02.001.001.P70-1215 [AF013368] 00.026.0.01.012. Dakar bat virus (DBV)00.026.0.01.012.03.003.001. 209 [AF013371] 00.026.0.01.031. Montanamyotis leukoencephalitis virus (MMLV) 00.026.0.01.031.03.001.001. 40649[AF013388] 00.026.0.01.035. Phnom Penh bat virus (PPBV)00.026.0.01.035.02.001.001. CAMA-38D [AF013394] 00.026.0.01.035.02.002.Batu Cave virus (BCV) 00.026.0.01.035.02.002.001. P70-1459 [AF013369]00.026.0.01.037. Rio Bravo virus (RBV) 00.026.0.01.037.03.003.001. M-64[AF013396] Unassigned Members in the Genus 00.026.0.81.056. Tamana batvirus (TABV) 00.026.0.81.057. Cell fusing agent virus [M91671] (CFAV)Genus 00.026.0.02. Pestivirus Type Species 00.026.0.02.001. Bovine viraldiarrhea virus 1 (BVDV) List of Species in the Genus The ICTVdB viruscode and the viruses. Official virus species names are in italics.Tentative virus species names, alternative names ( ), isolates, strains,serotypes, subspecies, or rejected names are not italicized. Viruscodes, virus names, arthropod vector and host names { }, serotypes,genome sequence accession numbers [ ] and assigned abbreviations ( ),are: Species, their serotypes, strains and isolates 00.026.0.02.002.Border disease virus (sheep) (BDV) 00.026.0.02.002.00.001.001. BD31[U70263] 00.026.0.02.002.00.001.002. X818 [AF037405] 00.026.0.02.003.Bovine viral diarrhea virus 1 (BVDV-1) 00.026.0.02.003.00.001.001. NADL[M31182] 00.026.0.02.003.00.001.002. Osloss [M96687]00.026.0.02.003.00.001.003. SD-1 [M96751] 00.026.0.02.003.00.001.004.CP7 [U63479] 00.026.0.02.004. Bovine viral diarrhea virus 2 (BVDV-2)00.026.0.02.004.00.001.001. strain 890 [U18059]00.026.0.02.004.00.001.002. C413 [AF002227] 00.026.0.02.005. Classicalswine fever virus (CSFV) 00.026.0.02.005.00.001.001. Alfort/187 [X87939]00.026.0.02.005.00.001.002. Alfort-Tubingen [J04358]00.026.0.02.005.00.001.003. Brescia [M31768] 00.026.0.02.005.00.001.004.C strain [Z46258] 00.026.0.02.005. (Hog cholera virus) (HCV) UnassignedMembers in the Genus 00.026.0.82.006. Pestivirus of giraffe (H138(Giraffe-1)) Genus 00.026.0.03. Hepacivirus Type Species00.026.0.03.001. Hepatitis C virus (HCV) List of Species in the GenusThe ICTVdB virus code and the viruses. Official virus species names arein italics. Tentative virus species names, alternative names ( ),isolates, strains, serotypes, subspecies, or rejected names are notitalicized. Virus codes, virus names, arthropod vector and host names {}, serotypes, genome sequence accession numbers [ ] and assignedabbreviations ( ), are: Species, their serotypes, strains and isolates00.026.0.03.001. Hepatitis C virus (HCV) 00.026.0.03.001.01. HCVgenotype 1 00.026.0.03.001.01.001. subtype 1a [M62321] (HCV-1)00.026.0.03.001.01.002. subtype 1b [D90208] (HCV-J) 00.026.0.03.001.02.HCV genotype 2 00.026.0.03.001.02.001. subtype 2a [D00944] (HCV-J6)00.026.0.03.001.02.002. subtype 2b [D01221] (HCV-J8) 00.026.0.03.001.03.HCV genotype 3 00.026.0.03.001.03.001. subtype 3a [D17763] (HCV-NZL1)00.026.0.03.001.03.010. subtype 10a [D63821] (HCV-JK049)00.026.0.03.001.04. HCV genotype 4 00.026.0.03.001.04.001. subtype 4a[Y11604] (HCV-ED43) 00.026.0.03.001.05. HCV genotype 500.026.0.03.001.05.001. subtype 5a [Y13184] (HCV-EVH1480)00.026.0.03.001.06. HCV genotype 6 00.026.0.03.001.06.001. subtype 6a[Y12083] (HCV-EUHK2) 00.026.0.03.001.06.011. subtype 11a [D63822](HCV-JK046) Unassigned Members in the Genus 00.026.0.83.002. GB virus B[U22304] (GBV-B) Unassigned Viruses in the Family 00.026.0.00.001. GBvirus A [U22303] (GBV-A) 00.026.0.00.002. GB virus B [U22304] (GBV-B) NoClassification Details available 00.026.0.84.002. GBV-A-like agents[U94421] (GBV-A-like agents) 00.026.0.06.001. GB virus C [U36380](GBV-C) 00.026.0.06.002. Hepatitis G virus [U44402] (HGV-1)00.026.0.06.001.00.000.001. GB virus C troglodytes [AF070476] (GBV-C)00.026.0.06.002.00.000.001. HGV-Iowan [AF121950] (HGV-Iowan)

TABLE 6 (from the ICTVdB Index of Viruses on the worldwide web atncbi.nlm.nih.gov/ICTVdb/Ictv/fs_picor.htm) Family 00.052. PicornaviridaeTaxonomic Structure of the Family Family 00.052. Picornaviridae Genus00.052.0.01. Enterovirus Genus 00.052.0.02. Rhinovirus Genus00.052.0.04. Cardiovirus Genus 00.052.0.05. Aphthovirus Genus00.052.0.03. Hepatovirus Genus 00.052.0.06. Parechovirus Genus00.052.0.07. Erbovirus Genus 00.052.0.08. Kobuvirus Genus 00.052.0.09.Teschovirus Genus 00.052.0.01. Enterovirus Type Species 00.052.0.01.001.Poliovirus (PV)http://rhino.bocklabs.wisc.edu/cgi-bin/virusworld/virustable.pl?virusdata=p1m%2C+Polio+Virus+Type+1+Mahoney%2C+2PLVList of Species in the Genus The ICTVdB virus code and the viruses.Official virus species names are in italics. Tentative virus speciesnames, alternative names ( ), isolates, strains, serotypes, subspecies,or rejected names are not italicized. Virus codes, virus names,arthropod vector and host names { }, serotypes, genome sequenceaccession numbers [ ] and assigned abbreviations ( ), are: Species,their serotypes, strains and isolates 00.052.0.01.002. Bovineenterovirus (BEV) 00.052.0.01.002.00.001. Bovine enterovirus 1 [D00214](BEV-1) 00.052.0.01.002.00.002. Bovine enterovirus 2 [X79369] (BEV-2)00.052.0.01.003. Human enterovirus A (HEV-A) 00.052.0.01.003.01.002.Human coxsackievirus A2 [L28146] (CV-A2) 00.052.0.01.003.01.002. Humancoxsackievirus A2 [X87585] (CV-A2) 00.052.0.01.003.01.003. Humancoxsackievirus A3 [X87586] (CV-A3) 00.052.0.01.003.01.005. Humancoxsackievirus A5 [X87588] (CV-A5) 00.052.0.01.003.01.007. Humancoxsackievirus A7 [X87589] (CV-A7) 00.052.0.01.003.01.008. Humancoxsackievirus A8 [X87590] (CV-A8) 00.052.0.01.003.01.010. Humancoxsackievirus A10 [X87591] (CV-A10) 00.052.0.01.003.01.012. Humancoxsackievirus A12 [X87593] (CV-A12) 00.052.0.01.003.01.014. Humancoxsackievirus A14 [X87595] (CV-A14) 00.052.0.01.003.01.016. Humancoxsackievirus A16 [U05876] (CV-A16) 00.052.0.01.003.00.071. Humanenterovirus 71 [U22521] (HEV71) 00.052.0.01.004. Human enterovirus B(HEV-B) 00.052.0.01.004.02.001. Human coxsackievirus B1 [M16560] (CV-B1)00.052.0.01.004.02.002. Human coxsackievirus B2 [AF081485] (CV-B2)00.052.0.01.004.02.003. Human coxsackievirus B3 [M88483] (CV-B3)00.052.0.01.004.02.004. Human coxsackievirus B4 [X05690] (CV-B4)00.052.0.01.004.02.005. Human coxsackievirus B5 [X67706] (CV-B5)(including Swine vesicular disease virus) 00.052.0.01.004.02.005. (Swinevesicular disease virus) [D00435] (CV-B5) 00.052.0.01.004.02.006. Humancoxsackievirus B6 [AF039205] (CV-B6) 00.052.0.01.004.01.009. Humancoxsackievirus A9 [D00627] (CV-A9) 00.052.0.01.004.03.001. Humanechovirus 1 [X89531] (EV-1) 00.052.0.01.004.03.002. Human echovirus 2[X89532] (EV-2) 00.052.0.01.004.03.003. Human echovirus 3 [X89533](EV-3) 00.052.0.01.004.03.004. Human echovirus 4 [X89534] (EV-4)00.052.0.01.004.03.005. Human echovirus 5 [X89535] (EV-5)00.052.0.01.004.03.006. Human echovirus 6 [U16283] (EV-6)00.052.0.01.004.03.007. Human echovirus 7 [X89538] (EV-7)00.052.0.01.004.03.009. Human echovirus 9 [X84981] (EV-9)00.052.0.01.004.03.009. Human echovirus 9 [X92886] (EV-9)00.052.0.01.004.03.011. Human echovirus 11 [X80059] (EV-11)00.052.0.01.004.03.012. Human echovirus 12 [X79047] (EV-12)00.052.0.01.004.03.013. Human echovirus 13 [X89542] (EV-13)00.052.0.01.004.03.014. Human echovirus 14 [X89543] (EV-14)00.052.0.01.004.03.015. Human echovirus 15 [X89544] (EV-15)00.052.0.01.004.03.016. Human echovirus 16 [X89545] (EV-16)00.052.0.01.004.03.017. Human echovirus 17 [X89546] (EV-17)00.052.0.01.004.03.018. Human echovirus 18 [X89547] (EV-18)00.052.0.01.004.03.019. Human echovirus 19 [X89548] (EV-19)00.052.0.01.004.03.020. Human echovirus 20 [X89549] (EV-20)00.052.0.01.004.03.021. Human echovirus 21 [X89550] (EV-21)00.052.0.01.004.03.024. Human echovirus 24 [X89551] (EV-24)00.052.0.01.004.03.025. Human echovirus 25 [X90722] (EV-25)00.052.0.01.004.03.025. Human echovirus 25 [X89552] (EV-25)00.052.0.01.004.03.026. Human echovirus 26 [X89553] (EV-26)00.052.0.01.004.03.027. Human echovirus 27 [X89554] (EV-27)00.052.0.01.004.03.029. Human echovirus 29 [X89555] (EV-29)00.052.0.01.004.03.030. Human echovirus 30 [X89556] (EV-30)00.052.0.01.004.03.031. Human echovirus 31 [X89557] (EV-31)00.052.0.01.004.03.032. Human echovirus 32 [X89558] (EV-32)00.052.0.01.004.03.033. Human echovirus 33 [X89559] (EV-33)00.052.0.01.004.03.069. Human enterovirus 69 [X87605] (HEV-69)00.052.0.01.005. Human enterovirus C (HEV-C) 00.052.0.01.005.01.001.Human coxsackievirus A1 [X87584] (CV-A1) 00.052.0.01.005.01.011. Humancoxsackievirus A11 [X87592] (CV-A11) 00.052.0.01.005.01.013. Humancoxsackievirus A13 [X87594] (CV-A13) 00.052.0.01.005.01.015. Humancoxsackievirus A15 [X87596] (CV-A15) 00.052.0.01.005.01.017. Humancoxsackievirus A17 [X87597] (CV-A17) 00.052.0.01.005.01.018. Humancoxsackievirus A18 [X87598] (CV-A18) 00.052.0.01.005.01.019. Humancoxsackievirus A19 [X87599] (CV-A19) 00.052.0.01.005.01.020. Humancoxsackievirus A20 [X87600] (CV-A20) 00.052.0.01.005.01.021. Humancoxsackievirus A21 [D00538] (CV-A21) 00.052.0.01.005.01.022. Humancoxsackievirus A22 [X87603] (CV-A 22) 00.052.0.01.005.01.024. Humancoxsackievirus A24 [X90457] (CV-A24) 00.052.0.01.006. Human enterovirusD (HEV-D) 00.052.0.01.006.00.068. Human enterovirus 68 [X87604] (HEV-68)00.052.0.01.006.00.070 Human enterovirus 70 [D00820] (HEV-70)00.052.0.01.010. Human enterovirus E (HEV-E) 00.052.0.01.010.00.001. A-2plaque virus (proposal withdrawn September 2001) [AF201894]00.052.0.01.007. Poliovirus (PV) 00.052.0.01.007.00.001. Humanpoliovirus 1 (HPV-1) 00.052.0.01.007.00.001.001. Mahoney strain [J02281](HPV-1) 00.052.0.01.007.00.002. Human poliovirus 2 (HPV-2)00.052.0.01.007.00.002.001. Lansing strain [M12197] (HPV-1)00.052.0.01.007.00.003. Human poliovirus 3 (HPV-3)00.052.0.01.007.00.003.001. P3/Leon/37 [K01392] (HPV-1) 00.052.0.01.008.Porcine enterovirus A (PEV-A) 00.052.0.01.008.00.008. Porcineenterovirus 8 [AJ001391] (PEV-8) 00.052.0.01.009. Porcine enterovirus B(PEV-B) 00.052.0.01.009.00.009. Porcine enterovirus 9 [Y14459] (PEV-9)00.052.0.01.009.00.010. Porcine enterovirus 10 (PEV-10) UnassignedMembers in the Genus Serotypes not yet assigned to a species00.052.0.01.103. Human coxsackievirus A 4 (CV-A4) 00.052.0.01.106. Humancoxsackievirus A 6 (CV-A6) 00.052.0.01.081. Simian enterovirus 1 (SEV-1)00.052.0.01.082. Simian enterovirus 2 (SEV-2) 00.052.0.01.083. Simianenterovirus 3 (SEV-3) 00.052.0.01.084. Simian enterovirus 4 (SEV-4)00.052.0.01.085. Simian enterovirus 5 (SEV-5) 00.052.0.01.086. Simianenterovirus 6 (SEV-6) 00.052.0.01.087. Simian enterovirus 7 (SEV-7)00.052.0.01.088. Simian enterovirus 8 (SEV-8) 00.052.0.01.089. Simianenterovirus 9 (SEV-9) 00.052.0.01.090. Simian enterovirus 10 (SEV-10)00.052.0.01.091. Simian enterovirus 11 (SEV-11) 00.052.0.01.092. Simianenterovirus 12 (SEV-12) 00.052.0.01.093. Simian enterovirus 13 (SEV-13)00.052.0.01.094. Simian enterovirus 14 (SEV-14) 00.052.0.01.095. Simianenterovirus 15 (SEV-15) 00.052.0.01.096. Simian enterovirus 16 (SEV-16)00.052.0.01.097. Simian enterovirus 17 (SEV-17) 00.052.0.01.098. Simianenterovirus 18 (SEV-18) 00.052.0.01.099. Simian enterovirus N125(SEV-N125) 00.052.0.01.100. Simian enterovirus N203 (SEV-N203) Genus00.052.0.02. Rhinovirus Type Species 00.052.0.02.001. Human rhinovirus A(HRV-1A) List of Species in the Genus The ICTVdB virus code and theviruses. Official virus species names are in italics. Tentative virusspecies names, alternative names ( ), isolates, strains, serotypes, orsubtypes are not italicized. Virus codes, virus names, arthropod vectorand host names { }, serotypes, genome sequence accession numbers [ ] andassigned abbreviations ( ), are: Species, their serotypes, strains andisolates 00.052.0.02.001. Human rhinovirus A (HRV-A)00.052.0.02.001.00.001. Human rhinovirus 1 (HRV-1)00.052.0.02.001.00.001.001. Human rhinovirus 1A (HRV-1A)00.052.0.02.001.00.001.002. Human rhinovirus 1B [D00239] (HRV-1B)00.052.0.02.001.00.002. Human rhinovirus 2 [X02316] (HRV-2)00.052.0.02.001.00.007. Human rhinovirus 7 [Z47564] (HRV-7)00.052.0.02.001.00.009. Human rhinovirus 9 (HRV-9)00.052.0.02.001.00.011. Human rhinovirus 11 [Z47565] (HRV-11)00.052.0.02.001.00.015. Human rhinovirus 15 (HRV-15)00.052.0.02.001.00.016. Human rhinovirus 16 [L24917] (HRV-16)00.052.0.02.001.00.021. Human rhinovirus 21 [Z47566] (HRV-21)00.052.0.02.001.00.029. Human rhinovirus 29 [Z47567] (HRV-29)00.052.0.02.001.00.036. Human rhinovirus 36 [Z49123] (HRV-36)00.052.0.02.001.00.039. Human rhinovirus 39 (HRV-39)00.052.0.02.001.00.049. Human rhinovirus 49 [Z47568] (HRV-49)00.052.0.02.001.00.050. Human rhinovirus 50 [Z47569] (HRV-50)00.052.0.02.001.00.058. Human rhinovirus 58 [Z47570] (HRV-58)00.052.0.02.001.00.062. Human rhinovirus 62 [Z47571] (HRV-62)00.052.0.02.001.00.065. Human rhinovirus 65 [Z47572] (HRV-65)00.052.0.02.001.00.085. Human rhinovirus 85 (HRV-85)00.052.0.02.001.00.089. Human rhinovirus 89 [M16248] (HRV-89)00.052.0.02.002. Human rhinovirus B (HRV-B) 00.052.0.02.002.00.003.Human rhinovirus 3 [U60874] (HRV-3) 00.052.0.02.002.00.014. Humanrhinovirus 14 [K02121] (HRV-14) 00.052.0.02.002.00.014. Human rhinovirus14 [K01087] (HRV-14) 00.052.0.02.002.00.014. Human rhinovirus 14[L05355] (HRV-14) 00.052.0.02.002.00.072. Human rhinovirus 72 [Z47574](HRV-72) Unassigned Members in the Genus Serotypes not yet assigned to aspecies 00.052.0.02.000.00.301. Bovine rhinovirus 1 (BRV-1)00.052.0.02.000.00.302. Bovine rhinovirus 2 (BRV-2)00.052.0.02.000.00.303. Bovine rhinovirus 3 (BRV-3)00.052.0.02.002.00.004. Human rhinovirus 4 (HRV-4)00.052.0.02.002.00.005. Human rhinovirus 5 (HRV-5)00.052.0.02.002.00.006. Human rhinovirus 6 (HRV-6)00.052.0.02.001.00.008. Human rhinovirus 8 (HRV-8)00.052.0.02.001.00.010. Human rhinovirus 10 (HRV-10)00.052.0.02.001.00.012. Human rhinovirus 12 (HRV-12)00.052.0.02.001.00.013. Human rhinovirus 13 (HRV-13)00.052.0.02.002.00.017. Human rhinovirus 17 (HRV-17)00.052.0.02.001.00.018. Human rhinovirus 18 (HRV-18)00.052.0.02.001.00.019. Human rhinovirus 19 (HRV-19)00.052.0.02.000.00.020. Human rhinovirus 20 (HRV-20)00.052.0.02.001.00.022. Human rhinovirus 22 (HRV-22)00.052.0.02.001.00.023. Human rhinovirus 23 (HRV-23)00.052.0.02.001.00.024. Human rhinovirus 24 (HRV-24)00.052.0.02.001.01.025. Human rhinovirus 25 (HRV-25)00.052.0.02.002.00.026. Human rhinovirus 26 (HRV-26)00.052.0.02.002.00.027. Human rhinovirus 27 (HRV-27)00.052.0.02.001.00.028. Human rhinovirus 28 (HRV-28)00.052.0.02.001.00.030. Human rhinovirus 30 (HRV-30)00.052.0.02.001.00.031. Human rhinovirus 31 [Z29658] (HRV-31)00.052.0.02.000.00.032. Human rhinovirus 32 (HRV-32)00.052.0.02.001.00.033. Human rhinovirus 33 (HRV-33)00.052.0.02.001.00.034. Human rhinovirus 34 (HRV-34)00.052.0.02.000.00.035. Human rhinovirus 35 (HRV-35)00.052.0.02.002.00.037. Human rhinovirus 37 (HRV-37)00.052.0.02.001.00.038. Human rhinovirus 38 (HRV-38)00.052.0.02.000.00.040. Human rhinovirus 40 (HRV-40)00.052.0.02.001.00.041. Human rhinovirus 41 (HRV-41)00.052.0.02.002.00.042. Human rhinovirus 42 (HRV-42)00.052.0.02.000.00.043. Human rhinovirus 43 (HRV-43)00.052.0.02.001.00.044. Human rhinovirus 44 [Z29660] (HRV-44)00.052.0.02.001.00.045. Human rhinovirus 45 (HRV-45)00.052.0.02.000.00.046. Human rhinovirus 46 (HRV-46)00.052.0.02.001.00.047. Human rhinovirus 47 (HRV-47)00.052.0.02.002.00.048. Human rhinovirus 48 (HRV-48)00.052.0.02.001.00.051. Human rhinovirus 51 (HRV-51)00.052.0.02.002.00.052. Human rhinovirus 52 (HRV-52)00.052.0.02.001.00.053. Human rhinovirus 53 (HRV-53)00.052.0.02.001.00.054. Human rhinovirus 54 (HRV-54)00.052.0.02.001.00.055. Human rhinovirus 55 (HRV-55)00.052.0.02.001.00.056. Human rhinovirus 56 (HRV-56)00.052.0.02.000.00.057. Human rhinovirus 57 (HRV-57)00.052.0.02.001.00.059. Human rhinovirus 59 (HRV-59)00.052.0.02.001.00.060. Human rhinovirus 60 (HRV-60)00.052.0.02.001.00.061. Human rhinovirus 61 (HRV-61)00.052.0.02.001.00.063. Human rhinovirus 63 (HRV-63)00.052.0.02.001.00.064. Human rhinovirus 64 (HRV-64)00.052.0.02.001.00.066. Human rhinovirus 66 (HRV-66)00.052.0.02.001.00.067. Human rhinovirus 67 (HRV-67)00.052.0.02.001.00.068. Human rhinovirus 68 (HRV-68)00.052.0.02.002.00.069. Human rhinovirus 69 (HRV-69)00.052.0.02.002.00.070. Human rhinovirus 70 (HRV-70)00.052.0.02.001.00.071. Human rhinovirus 71 (HRV-71)00.052.0.02.001.00.073. Human rhinovirus 73 (HRV-73)00.052.0.02.001.00.074. Human rhinovirus 74 (HRV-74)00.052.0.02.001.00.075. Human rhinovirus 75 (HRV-75)00.052.0.02.001.00.076. Human rhinovirus 76 (HRV-76)00.052.0.02.001.00.077. Human rhinovirus 77 (HRV-77)00.052.0.02.001.00.078. Human rhinovirus 78 (HRV-78)00.052.0.02.002.00.079. Human rhinovirus 79 (HRV-79)00.052.0.02.000.00.080. Human rhinovirus 80 (HRV-80)00.052.0.02.000.00.081. Human rhinovirus 81 (HRV-81)00.052.0.02.000.00.082. Human rhinovirus 82 (HRV-82)00.052.0.02.000.00.083. Human rhinovirus 83 (HRV-83)00.052.0.02.000.00.084. Human rhinovirus 84 (HRV-84)00.052.0.02.002.00.086. Human rhinovirus 86 (HRV-86)00.052.0.02.000.00.087. Human rhinovirus 87 [AF108187] (HRV-87)00.052.0.02.000.00.088. Human rhinovirus 88 (HRV-88)00.052.0.02.000.00.090. Human rhinovirus 90 (HRV-90)00.052.0.02.000.00.091. Human rhinovirus 91 (HRV-91)00.052.0.02.000.00.092 Human rhinovirus 92 (HRV-92)00.052.0.02.000.00.093. Human rhinovirus 93 (HRV-93)00.052.0.02.000.00.094. Human rhinovirus 94 (HRV-94)00.052.0.02.000.00.095. Human rhinovirus 95 (HRV-95)00.052.0.02.000.00.096. Human rhinovirus 96 (HRV-96)00.052.0.02.000.00.097. Human rhinovirus 97 (HRV-97)00.052.0.02.000.00.098. Human rhinovirus 98 (HRV-98)00.052.0.02.000.00.099. Human rhinovirus 99 (HRV-99)00.052.0.02.000.00.100. Human rhinovirus 100 (HRV-100) Genus00.052.0.04. Cardiovirus Type Species 00.052.0.04.001.Encephalomyocarditis virus (EMCV) List of Species in the Genus TheICTVdB virus code and the viruses. Official virus species names are initalics. Tentative virus species names, alternative names ( ), isolates,strains, serotypes, subspecies, or rejected names are not italicized.Virus codes, virus names, arthropod vector and host names { },serotypes, genome sequence accession numbers [ ] and assignedabbreviations ( ), are: Species, their serotypes, strains and isolates00.052.0.04.001. Encephalomyocarditis virus [M81861] (EMCV)00.052.0.04.001.00.001.002. Mengovirus 00.052.0.04.001.00.001.001.Columbia SK virus 00.052.0.04.001.00.001.003. Maus Elberfield virus00.052.0.04.002. Theilovirus (ThV) 00.052.0.04.002.00.002.001. Theiler'smurine encephalomyelitis virus (TMEV) [M20562]00.052.0.04.002.00.002.002. Vilyuisk human encephalomyelitis virus(VHEV) [M80888] 00.052.0.04.002.00.002.002. Vilyuisk humanencephalomyelitis virus (VHEV) [M94868] 00.052.0.04.002.00.002.003. Ratencephalomyelitis virus [M80884] (REV) Unassigned Members in the GenusNone reported. Genus 00.052.0.05. Aphthovirus Type Species00.052.0.05.001. Foot-and-mouth disease virus (FMDV) List of Species inthe Genus The ICTVdB virus code and the viruses. Official virus speciesnames are in italics. Tentative virus species names, alternative names (), isolates, strains, serotypes, subspecies, or rejected names are notitalicized. Virus codes, virus names, arthropod vector and host names {}, serotypes, genome sequence accession numbers [ ] and assignedabbreviations ( ), are: Species, their serotypes, strains and isolates00.052.0.05.002. Equine rhinitis A virus [L43052] (ERAV)00.052.0.05.002. Equine rhinitis A virus [X96870] 00.052.0.05.002.(formerly Equine rhinovirus 1 virus) (ERV-1) 00.052.0.05.003.Foot-and-mouth disease virus (FMDV) 00.052.0.05.003.00.002.Foot-and-mouth disease virus A [M10975] (FMDV-A) 00.052.0.05.003.00.002.Foot-and-mouth disease virus A [L11360] 00.052.0.05.003.00.004.Foot-and-mouth disease virus Asia 1 [U01207] (FMDV-Asia1)00.052.0.05.003.00.003. Foot-and-mouth disease virus C [X00130] (FMDV-C)00.052.0.05.003.00.003. Foot-and-mouth disease virus C [J02191]00.052.0.05.003.00.001. Foot-and-mouth disease virus O [M35873] (FMDV-O)00.052.0.05.003.00.001. Foot-and-mouth disease virus O [X00871]00.052.0.05.003.00.005. Foot-and-mouth disease virus SAT 1 [Z98203](FMDV-SAT1) 00.052.0.05.003.00.006. Foot-and-mouth disease virus SAT 2[AJ251473] (FMDV-SAT2) 00.052.0.05.003.00.007. Foot-and-mouth diseasevirus SAT 3 [M28719] (FMDV-SAT3) Unassigned Members in the Genus Nonereported. Genus 00.052.0.03. Hepatovirus Type Species 00.052.0.03.001.Hepatitis A virus (HAV) List of Species in the Genus The ICTVdB viruscode and the viruses. Official virus species names are in italics.Tentative virus species names, alternative names ( ), isolates, strains,serotypes, subspecies, or rejected names are not italicized. Viruscodes, virus names, arthropod vector and host names { }, serotypes,genome sequence accession numbers [ ] and assigned abbreviations ( ),are: Species, their serotypes, strains and isolates 00.052.0.03.001.Hepatitis A virus (HAV) 00.052.0.03.001.00.001.001. Human hepatitis Avirus [M14707] (HHAV) 00.052.0.03.001.00.001.002. Simian hepatitis Avirus [D00924] (SHAV) Unassigned Members in the Genus 00.052.0.83.003.Avian encephalomyelitis-like virus [AJ225173] (AEV) Genus 00.052.0.06.Parechovirus Type Species 00.052.0.06.001. Human parechovirus (HPeV)List of Species in the Genus The ICTVdB virus code and the viruses.Official virus species names are in italics. Tentative virus speciesnames, alternative names ( ), isolates, strains, serotypes, subspecies,or rejected names are not italicized. Virus codes, virus names,arthropod vector and host names { }, serotypes, genome sequenceaccession numbers [ ] and assigned abbreviations ( ), are: Species,their serotypes, strains and isolates 00.052.0.06.001. Humanparechovirus (HPeV) 00.052.0.06.001.00.001. Human parechovirus type 1[L02971] (HPeV-1) was 00.052.0.01.052. (formerly Human echovirus 22)(EV-22) 00.052.0.06.001.00.002. Human parechovirus type 2 [AJ005695](HPeV-2) was 00.052.0.01.053. (formerly Human echovirus 23) (EV-23)00.052.0.06.0.003. Ljungan virus [AF020541] (LjV) 00.052.0.06.0.003.(Rodent parechovirus) (RPeV) was 00.052.0.86.022. Ljungan virus (LV)Unassigned Members in the Genus None reported. Genus 00.052.0.07.Erbovirus Type Species 00.052.0.007.001. Equine rhinitis B virus (ERBV)List of Species in the Genus The ICTVdB virus code and the viruses.Official virus species names are in italics. Tentative virus speciesnames, alternative names ( ), isolates, strains, serotypes, subspecies,or rejected names are not italicized. Virus codes, virus names,arthropod vector and host names { }, serotypes, genome sequenceaccession numbers [ ] and assigned abbreviations ( ), are: Species,their serotypes, strains and isolates 00.052.0.07.001. Equine rhinitis Bvirus [X96871] (ERBV) was 00.052.0.00.004. (formerly Equine rhinovirus2) (ERV-2) Unassigned Members in the Genus None reported. Genus00.052.0.08. Kobuvirus Type Species 00.052.0.08.001. Aichi virus (AiV)List of Species in the Genus The ICTVdB virus code and the viruses.Official virus species names are in italics. Tentative virus speciesnames, alternative names ( ), isolates, strains, serotypes, subspecies,or rejected names are not italicized. Virus codes, virus names,arthropod vector and host names { }, serotypes, genome sequenceaccession numbers [ ] and assigned abbreviations ( ), are: Species,their serotypes, strains and isolates 00.052.0.08.001. Aichi virus[AB010145] (AiV) Unassigned Members in the Genus None reported. Genus00.052.0.09. Teschovirus Type Species 00.052.0.09.001. Porcineteschovirus 1 (PTV) List of Species in the Genus The ICTVdB virus codeand the viruses. Official virus species names are in italics. Tentativevirus species names, alternative names ( ), isolates, strains,serotypes, subspecies, or rejected names are not italicized. Viruscodes, virus names, arthropod vector and host names { }, serotypes,genome sequence accession numbers [ ] and assigned abbreviations ( ),are: Species, their serotypes, strains and isolates 00.052.0.09.001.Porcine teschovirus 1 [AJ011380] (PTV-1) was 00.052.0.01.070. (formerlyPorcine enterovirus 1) (PEV-1) 00.052.0.09.002. Porcine teschovirus 2(PTV-2) was 00.052.0.01.071. (formerly Porcine enterovirus 2) (PEV-2)00.052.0.09.003. Porcine teschovirus 3 (PTV-3) was 00.052.0.01.072(formerly Porcine enterovirus 3) (PEV-3) 00.052.0.09.004. Porcineteschovirus 4 (PTV-4) was 00.052.0.01.073. (formerly Porcine enterovirus4) (PEV-4) 00.052.0.09.005. Porcine teschovirus 5 (PTV-5) was00.052.0.01.074. (formerly Porcine enterovirus 5) (PEV-5)00.052.0.09.006. Porcine teschovirus 6 (PTV-6) was 00.052.0.01.075.(formerly Porcine enterovirus 6) (PEV-6) 00.052.0.09.007. Porcineteschovirus 7 (PTV-7) was 00.052.0.01.076. (formerly Porcine enterovirus7) (PEV-7) 00.052.0.09.008. Porcine teschovirus 11 (PTV-11) was00.052.0.01.080. (formerly Porcine enterovirus 11) (PEV-11)00.052.0.09.009. Porcine teschovirus 12 (PTV-12) (formerly Porcineenterovirus 12) (PEV-12) 00.052.0.09.010. Porcine teschovirus 13(PTV-13) (formerly Porcine enterovirus 13) (PEV-13) Unassigned Membersin the Genus None reported. List of Unassigned Viruses in the Family00.052.0.00.010. Acid-stable equine picornaviruses (EqPV)00.052.0.00.011. Avian entero-like virus 2 (AELV-2) 00.052.0.00.012.Avian entero-like virus 3 (AELV-3) 00.052.0.00.013. Avian entero-likevirus 4 (AELV-4) 00.052.0.00.034. Avian nephritis virus 1 (ANV-1)00.052.0.00.014. Avian nephritis virus 2 (ANV-2) 00.052.0.00.015. Aviannephritis virus 3 (ANV-3) 00.052.0.00.016. Barramundi virus-1+ (BaV)00.052.0.00.017. Cockatoo entero-like virus (CELV) 00.052.0.00.018. Duckhepatitis virus 1 (DHV-1) 00.052.0.00.019. Duck hepatitis virus 3(DHV-3) 00.052.0.00.005. Equine rhinovirus 3 (ERV-3) 00.052.0.00.020.Guineafowl transmissible enteritis virus (GTEV) 00.052.0.00.021. Harbourseal picorna-like virus (SPLV) 00.052.0.86.022. Ljungan virus**[AF020541] (LV) 00.052.0.00.023. Sea-bass virus-1+ (SBV)00.052.0.00.024. Sikhote-Alyn virus (SAV) 00.052.0.00.025. Smeltvirus-1+ (SmV-1) 00.052.0.00.026. Smelt virus-2+ (SmV-2)00.052.0.00.027. Syr-Daria Valley fever virus (SDFV) 00.052.0.00.028.Taura syndrome virus of marine penaeid shrimp (TSV) 00.052.0.00.029.Turbot virus-1 (TuV-1) 00.052.0.00.030. Turkey entero-like virus (TELV)00.052.0.00.031. Turkey hepatitis virus (THV) 00.052.0.00.032. Turkeypseudo enterovirus 1 (TPEV-1) 00.052.0.00.033. Turkey pseudo enterovirus2 (TPEV-2)

EXAMPLES Example 1 Immediate Release Tablet and Optionally SubsequentFilm-Coating 1.1 Composition of tablets containing the p-toluenesulfonicacid salt of4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide

Composition [mg/tablet] Tablet A 50 mg Tablet B 200 mg Tablet C 200 mgTablet D 400 mg Tablet core: step a), b) step a), b), c) ii Step a), b)c) i Step a), b) c) i Tosylate salt of compound 68.5 mg 274.0 mg  274.0mg  548.0 mg  (I) micronized Microcrystalline cellulose  4.0 mg 16.0 mg16.0 mg 32.0 mg Croscarmellose sodium  9.1 mg 36.4 mg 36.4 mg 72.8 mgHypromellose (5 cP) 2.55 mg 10.2 mg 10.2 mg 20.4 mg Magnesium stearate0.425 mg   1.7 mg  2.55 mg^(#1) 5.10 mg  (1.70-2.55 mg) Sodium laurylsulfate 0.425 mg   1.7 mg  1.7 mg  3.4 mg Weight 85.0 mg 340.0 mg 340.85 mg  681.70 mg  (340.0-340.85 mg)  Film-coating: Opadry RedYS2-15531^(#3) — 10.0 mg —^(#2)— —^(#2)— Hypromellose (15 cP) — — 6.00mg  9.0 mg   (4.8-7.2 mg)  (7.2-10.8 mg) Macrogol 3350 — — 2.00 mg  3.0mg (polyethylene gycol)   (1.6-2.4 mg)  (2.4-3.6 mg) Titanium dioxide —— 1.73 mg  1.6 mg (1.384-2.076 mg) (1.28-1.92 mg) Ferric oxide (red) — —0.27 mg — (0.216-0.324 mg) Ferric oxide (yellow) — — —  1.4 mg(1.12-1.68 mg) Weight of film coat — 10.0 mg 10.0 mg 15.0 mg   (8.0-12.0mg) (12.0-18.0 mg) Total tablet weight 85.0 mg 350.0 mg  350.85 mg 696.7 mg  (348-352.85 mg) (348.0-352.85 mg)   Tablet format Round roundround oval Dimensions of the tablet diameter: 6 mm diameter: 10 mm,diameter: 10 mm, length: 18 mm, height: 4.5 (±0.3) mm height: 4.5 (±0.3)mm width: 8 mm ^(#1)Range for Mg stearate may apply according tomanufacturing conditions ^(#2)Range for film coat may apply according tomanufacturing conditions Fixed ratio of coating components 60%(hypromellose) - 20% (polyethylene glycol) - 17.3% (titanium dioxide) -2.7% ferric oxide ^(#3)Opadry Red YS-15531 ready to use commercialcoating system.

1.2 Process for Manufacturing Step a) Granulation

4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylicacid methyl amide micronized, microcrystalline cellulose, croscarmellosesodium, and hypromellose are mixed for 2 minutes in a high shear mixerin order to obtain a powder blend. Sodium lauryl sulfate is dissolved inwater. The powder blend is granulated with the solution in a wetgranulation process using a high-shear mixer. The granulation process isfinished when the granulate achieves a “snow ball like consistency”. Thewet granulation mass is sized using a 4 mm rasp and then dried in afluidized bed dryer at an inlet air temperature of 80-100° C. until aresidual moisture of 0.3 up to 0.7% by weight (loss on drying) isreached. The dry granules are sieved using a 2 mm sieve size.

Step b) Tablet Compression

The granulate is blended with magnesium stearate and croscarmellosesodium using a tumbler blender for from 5 to 10 minutes. The blend issubdivided into single units and compressed to tablets using a standardrotary tablet press at typical tabletting speeds of from 25,000 to250,000 tablets/hour.

Step c) Film-Coating Alternative i:

Hypromeilose, polyethylene glycol (Macrogol), titanium dioxide andferric oxide red are combined with purified water to result in ahomogenous coating suspension which is sprayed on the tablets in aperforated drum coater.

Alternative ii:

The commercially available Opadry Red YS-15531 is combined with purifiedwater to result in a homogenous coating suspension which is sprayed onthe tablets in a perforated drum coater.

1. A method of treating hepatitis virus infections and/or inflammationcaused by hepatitis virus infections comprising administering to a humanor other mammal in need thereof a compound of formula I or apharmaceutically acceptable salt, polymorph, solvate, hydrate,metabolite, prodrug or diastereoisomeric form thereof, wherein saidcompound of formula I is:

wherein Q is —C(O)R_(x) R_(x) is hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy orNR_(a)R_(b), R_(a) and R_(b) are independently: a) hydrogen; b) C₁₋₄alkyl, optionally substituted by -hydroxy, —C₁₋₄ alkoxy, a heteroarylgroup selected from pyrrole, furan, thiophene, imidazole, pyrazole,thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole,thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine,triazine, benzoxazole, isoquioline, quinolines and imidazopyrimidine aheterocyclic group selected from tetrahydropyran, tetrahydrofuran,1,3-dioxolane, 1,4-dioxane, morpholine, thiomorpholine, piperazine,piperidine, piperidinone, tetrahydropyrimidone, pentamethylene sulfide,tetramethylene sulfide, dihydropyrane, dihydrofuran, anddihydrothiophene, amino, —NH₂, optionally substituted by one or two C₁₋₄alkyl groups, or phenyl, c) phenyl optionally substituted with halogen,or amino, —NH₂, optionally substituted by one or two C₁₋₄ alkyl, or d)—aheteroaryl group selected from pyrrole, furan, thiophene, imidazole,pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole,tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine,pyrazine, triazine, benzoxazole, isoquioline, quinoline andimidazopyrimidine; A is an optionally substituted phenyl group offormula 1xx:

 an optionally substituted pyridinyl group of formula 1x:

 or an optionally substituted naphthyl moiety of formula 1y:

B is optionally substituted phenyl or naphthyl of formulas 2a and 2b:

L is a bridging group which is —S— or —O—, p is 0, 1, 2, 3, or 4, n is0, 1, 2, 3, 4, 5 or 6, m is 0, 1, 2 or 3, each R¹ is independently:halogen, C₁₋₅ haloalkyl, NO₂, C(O)NR⁴R⁵, C₁₋₆ alkyl, C₁₋₆ dialkylamine,C₁₋₃ alkylamine, CN, amino, hydroxy or C₁₋₃alkoxy, each R² isindependently: C₁₋₅ alkyl, C₁₋₅ haloalkyl, C₁₋₃ alkoxy, N-oxo orN-hydroxy, each R³ is independently: halogen, R⁴, OR⁴, S(O)R⁴, C(O)R⁴,C(O)NR⁴R⁵, oxo, cyano or nitro (NO₂) and R⁴ and R⁵ are independentlyhydrogen, C₁₋₆ alkyl, or up to per-halogenated C₁₋₆ alkyl.
 2. A methodof claim 1 wherein A is 3-tert butyl phenyl, 5-tertbutyl-2-methoxyphenyl, 5-(trifluoromethyl)-2 phenyl,3-(trifluoromethyl)-4 chlorophenyl, 3-(trifluoromethyl)-4-bromophenyl or5-(trifluoromethyl)-4-chloro-2 methoxyphenyl; B is

R¹ is fluorine, chorine, bromine, methyl, NO₂, C(O)NH₂, methoxy, SCH₃,trifluoromethyl, or methanesulfonyl; R² is methyl, ethyl, propyl,oxygen, or cyano and R³ is trifluoromethyl, methyl, ethyl, propyl,butyl, isopropyl, tert-butyl, chlorine, fluorine, bromine, cyano,methoxy, acetyl, trifluoromethanesulfonyl, trifluoro-methoxy, ortrifluoromethylthio.
 3. A method of claim 1 wherein the compound offormula I is also of formula II below or salts, polymorphs, solvates,hydrates, metabolites, prodrugs or diastereoisomeric forms thereof:

wherein R^(a) and R^(b) are independently hydrogen and C₁-C₄ alkyl, B offormula II is

wherein the urea group, —NH—C(O)—NH—, and the oxygen bridging group arenot bound to contiguous ring carbons of B, but rather have 1 or 2 ringcarbons separating them, and A of formula (II) is

or

wherein the variable n is 0, 1, 2, 3 or 4, and R³ is trifluoromethyl,methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, chlorine, fluorine,bromine, cyano, methoxy, acetyl, trifluoromethanesulfonyl,trifluoromethoxy, or trifluoromethylthio.
 4. A method of claim 1wherein, each R³ substituent is chlorine, trifluoromethyl, tert-butyl ormethoxy, A of formula II is

and B of formula II is phenylene, fluoro substituted phenylene ordifluoro substituted phenylene.
 5. A method of claim 1 wherein thecompound of formula I is also of formula X below or salts, polymorphs,solvates, hydrates, metabolites, prodrugs or diastereoisomeric formsthereof:

wherein phenyl ring “B” optionally has one halogen substituent, A is anoptionally substituted phenyl group of formula 1xx:

an optionally substituted pyridinyl group of formula 1x:

or an optionally substituted naphthyl moiety of formula 1y:

n is 0, 1, 2, 3, 4, 5 or 6, m is 0, 1, 2 or 3, each R² is independently:C₁₋₅ alkyl, C₁₋₅ haloalkyl, C₁₋₃ alkoxy, N-oxo or N-hydroxy, each R³ isindependently: halogen, R⁴, OR⁴, S(O)R⁴, C(O)R⁴, C(O)NR⁴R⁵, oxo, cyanoor nitro (NO₂) and R⁴ and R⁵ are independently hydrogen, C₁₋₆ alkyl, orup to per-halogenated C₁₋₆ alkyl.
 6. A method of claim 5 wherein m iszero and A is substituted phenyl with at least one substituent R³.
 7. Amethod of claim 6 wherein R³ is halogen, trifluoromethyl and/or methoxy.8. A method of claim 1 wherein the compound of formula I also has thestructure of one of formulas Z1 or Z2 below or a salt, polymorph,solvate, hydrate, metabolite, prodrug or diastereoisomeric form thereof:


9. A method of claim 8 wherein the compound of formula I is the tosylatesalt of the compound of formula Z1.
 10. Combination comprising at leastone compound of formula I as defined in claim 1 and at least onetherapeutic agent selected from the group consisting of anti-viralagents, corticosteroids, immunomodulatory agents and known drugs for thetherapy of hepatitis virus infections and/or inflammation caused byhepatitis virus infections.
 11. (canceled)
 12. (canceled) 13.Combination of claim 10 wherein the further therapeutic agent isselected from the group consisting of adevovir dipivoxil, oseltamvir,zanamivir, acyclovir, valacyclovir, peniciclovir, famicilovir,foscarnet, brivudin, ganciclovir, cidofovir, imiquimod, resiquimod,podophyllin, bleomycin and retinoid, interferon (interferon-β,interferon alfacon-1, interferon-α and pegylated interferon-α),ribavirin, ruprintrivir (AG 7088), pirodavir, pleconaril, solubleICAM-1, lamivudin, parapoxvirus ovis, abacavir, tenofovir disproxilfumarat, emtricitabine, didanosine, stavudine, zidovudine, zalcitabine,efavirenz, nivirapine, delaviridine, atazanavir, ritonavir, amprenavir,lopinavir, rironavir, nelfinavir, indinavir, saquinavir, enfuvirtide,etravirine, capravirine and tenofovir.
 14. (canceled)
 15. (canceled) 16.(canceled)
 17. (canceled)
 18. (canceled)
 19. (canceled)
 20. (canceled)21. (canceled)
 22. (canceled)
 23. (canceled)
 24. A method of treatinghepatitis virus infections and/or inflammation caused hepatitis by virusinfections comprising administering to a human or other mammal in needthereof a combination of at least one compound of formula I as definedin claim 1 and at least one therapeutic agent selected from the groupconsisting of anti-viral agents, corticosteroids, immunomodulatoryagents and known drugs for the therapy of hepatitis virus infectionsand/or inflammation caused by hepatitis virus infections.
 25. (canceled)26. (canceled)
 27. (canceled)
 28. (canceled)
 29. (canceled) 30.(canceled)
 31. (canceled)
 32. (canceled)
 33. (canceled)
 34. (canceled)35. (canceled)
 36. (canceled)
 37. A pharmaceutical compositioncomprising a combination as defined in claim 10 for the treatment ofhepatitis virus infections and/or inflammation caused by hepatitis virusinfections.
 38. A pharmaceutical composition comprising a combination asdefined in claim 13 for the treatment of hepatitis virus infectionsand/or inflammation caused by said hepatitis virus infections.
 39. Amethod for treating of hepatitis virus infections and/or inflammationcaused by hepatitis virus infections in a human in need thereofcomprising administering effective amounts of at least one compound offormula I or a pharmaceutically acceptable salt, polymorph, solvate,hydrate, metabolite, prodrug or diastereoisomeric form thereof whereinsaid compound of formula I is:

wherein Q is —C(O)R, R_(x) is hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy orNR_(a)R_(b), R_(a) and R_(b) are independently: a) hydrogen; b) C₁₋₄alkyl, optionally substituted by hydroxy, C₁₋₄ alkoxy, a heteroarylgroup selected from pyrrole, furan, thiophene, imidazole, pyrazole,thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole,thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine,triazine, benzoxazole, isoquioline, quinolines and imidazopyrimidine aheterocyclic group selected from tetrahydropyran, tetrahydrofuran,1,3-dioxolane, 1,4-dioxane, morpholine, thiomorpholine, piperazine,piperidine, piperidinone, tetrahydropyrimidone, pentamethylene sulfide,tetramethylene sulfide, dihydropyrane, dihydrofuran, anddihydrothiophene, amino, —NH₂, optionally substituted by one or two C₁₋₄alkyl groups, or phenyl, c) phenyl optionally substituted with halogen,or amino, —NH₂, optionally substituted by one or two C₁₋₄ alkyl, or d)—aheteroaryl group selected from pyrrole, furan, thiophene, imidazole,pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole,tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine,pyrazine, triazine, benzoxazole, isoquioline, quinoline andimidazopyrimidine; A is an optionally substituted phenyl group offormula 1xx:

an optionally substituted pyridinyl group of formula 1x:

or an optionally substituted naphthyl moiety of formula 1y:

B is optionally substituted phenyl or naphthyl of formulas 2a and 2b:

L is a bridging group which is —S— or —O—, p is 0, 1, 2, 3, or 4, n is0, 1, 2, 3, 4, 5 or 6, m is 0, 1, 2 or 3, each R¹ is independently:halogen, C₁₋₅ haloalkyl, NO₂, C(O)NR⁴R⁵, C₁₋₆ alkyl, C₁₋₆ dialkylamine,C₁₋₃ alkylamine, CN, amino, hydroxy or C₁₋₃ alkoxy, each R² isindependently: C₁₋₅ alkyl, C₁₋₅ haloalkyl, C₁₋₃ alkoxy, N-oxo orN-hydroxy, each R³ is independently: halogen, R⁴, OR⁴, S(O)R⁴, C(O)R⁴,C(O)NR⁴R⁵, oxo, cyano or nitro (NO₂) and R⁴ and R⁵ are independentlyhydrogen, C₁₋₆ alkyl, or up to per-halogenated C₁₋₆ alkyl.
 40. Themethod of claim 39 wherein the compound of formula I is combined with atleast one therapeutic agent selected from the group consisting ofanti-viral agents, corticosteroids, immunomodulatory agents and knowndrugs for the therapy of virus infections and/or diseases caused byvirus infections.
 41. (canceled)
 42. (canceled)